Drug Interactions with Benzodiazepines: Epidemiologic Correlates with Other CNS Depressants and In Vitro Correlates with Inhibitors and Inducers of Cytochrome P450 3A4



The benzodiazepines are a class of a relatively large number of drugs that share a common chemical structure and have anxiolytic to sedative action on the central nervous system (CNS). They are chemically diverse, but share a classic structure that consists of a benzene fused to a seven-membered diazepine ring. Benzodiazepines are noted to have both pharmacodynamic and pharmacokinetic drug interactions. The former can be most devastating, and usually arise from co-exposure to another CNS depressant (e.g., ethanol, opioids, barbiturates, anesthe­tics). These have been associated with enhanced impairment and mortality, usually from respiratory depression. Pharmacodynamic interactions occur with all benzodiazepines and are not related to their structure. Pharmacokinetic interactions, on the other hand are highly structure dependent, as most arise from either inhibition or induction of the cytochrome P450s involved in the metabolism of the benzodiazepine. Numerous examples of pharmacokinetic interactions that alter the pharmacokinetics of the benzodiazepine have been reported and these are herein described for an assortment of drug. These interactions may have sufficient changes to significantly reduce efficacy (induction of metabolism), but toxicity from inhibition of metabolism was rarely seen at the therapeutic doses used in clinical studies. These consequences, however, could be magnified in the overuser. Numerous drug interactions between benzodiazepines and other drugs do occur; those with other CNS depressants are of greatest concern.


Benzodiazepines Drug interactions Drug metabolism Respiratory depression 


  1. 1.
    Greenblatt DJ, Shader RI, and Abernethy DR. Drug Therapy. Current status of benzodiazepines. First of two parts. N Engl J Med, 309: 354–358 (1983).PubMedGoogle Scholar
  2. 2.
    Greenblatt DJ, Shader RI, and Abernethy DR. Drug Therapy. Current status of benzodiazepines. Second of two parts. N Eng J of Med, 309: 410–416 (1983).Google Scholar
  3. 3.
    Jones GR, and Singer PP. The newer benzodiazepines. In Analytical Toxicology, 2., Baselt RC, Ed. Year Book Medical Publishers, Chicago, 1989, pp. 1–69.Google Scholar
  4. 4.
    Hobbs WR, Rall TW, and Verdoorn TA. Hypnotics and sedatives: ethanol. In Goodman & Gilman’s The Pharmacological Basis of Therapeutics, Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, and Gilman AG, Ed. McGraw-Hill, New York, 1996, pp. 361–396.Google Scholar
  5. 5.
    Benet LZ, Oie S, and Schwartz JB. Design and optimization of dosage regimes: pharmacokinetic data. In Goodman & Gilman’s The Pharmacological Basis of Therapeutics, Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, and Gilman AG, Ed. McGraw-Hill, New York, 1996, pp. 1707–1792.Google Scholar
  6. 6.
    Baselt RC, and Cravey RH. Disposition of toxic drugs and chemicals in man. Chemical Toxicology Institute, Foster City, CA, 1995.Google Scholar
  7. 7.
    Parfitt K. Martindale The Complete Drug Reference. (1999).Google Scholar
  8. 8.
    Murray L. Physicians’ Desk Reference. (2002).Google Scholar
  9. 9.
    ® TM. Healthcare Series. (2009).Google Scholar
  10. 10.
    Ishigami M, Honda T, Takasaki W, Ikeda T, Komai T, Ito K, and Sugiyama Y. A comparison of the effects of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-COA) reductase inhibitors on the CYP3A4-dependent oxidation of mexazolam in vitro. Drug Metab Dispos, 29: 282–288 (2001).PubMedGoogle Scholar
  11. 11.
    Sethy VH, Collins RJ, and Daniels EG. Determination of biological activity of adinazolam and its metabolites. J Pharm Pharmacol, 36: 546–548 (1984).PubMedGoogle Scholar
  12. 12.
    Fleishaker JC, and Phillips JP. Adinazolam pharmacokinetics and behavioral effects following administration of 20–60 mg doses of its mesylate salt in volunteers. Psychopharmacology, 99: 34–39 (1989).PubMedGoogle Scholar
  13. 13.
    Borchers F, Achtert G, Hausleiter HJ, and Zeugner H. Metabolism and pharmacokinetics of metaclazepam (Talis®), Part III: Determination of the chemical structure of metabolites in dogs, rabbits and men. Eur J Drug Metab Pharmacokinet, 9: 325–346 (1984).PubMedGoogle Scholar
  14. 14.
    Lu X-L, and Yang SK. Enantiomer resolution of camazepam and its derivatives and enantioselective metabolism of camazepam by (HLM). J Chromatogr A, 666: 249–257 (1994).PubMedGoogle Scholar
  15. 15.
    Tomori E, Horvath G, Elekes I, Lang T, and Korosi J. Investigation of the metabolites of tofizopam in man and animals by gas-liquid chromatography-mass spectrometry. J Chromatogr A, 241: 89–99 (1982).Google Scholar
  16. 16.
    Wrighton SA, Vandenbranden M, Stevens JC, Shipley LA, Ring BJ, Rettie AE, and Cashman JR. In vitro methods for assessing human drug metabolism: their use in drug development. Drug Metab Rev, 25: 453–484 (1993).PubMedGoogle Scholar
  17. 17.
    Rodrigues AD. Use of in vivo human metabolism studies in drug development: an industrial perspective. Biochem Pharmacol, 48: 2147–2156 (1994).PubMedGoogle Scholar
  18. 18.
    Guengerich FP. In vitro techniques for studying drug metabolism. J Pharmacokin Biopharm, 24: 521–533 (1996).Google Scholar
  19. 19.
    Crespi CL, and Miller VP. The use of heterologously expressed drug metabolizing enzymes – state of the art and prospects for the future. Pharmacol Ther, 84: 121–131 (1999).PubMedGoogle Scholar
  20. 20.
    Venkatakrishnan K, Von Moltke LL, Court MH, Harmatz JS, Crespi CL, and Greenblatt DJ. Comparison between cytochrome P450 (CYP) content and relative activity approaches to scaling from cDNA-expressed CYPs to (HLM): ratios of accessory proteins as sources of discrepancies between approaches. Drug Metab Dispos, 28: 1493–1504 (2000).PubMedGoogle Scholar
  21. 21.
    Nelson AC, Huang W, and Moody DE. Variables in human liver microsome preparation: impact on the kinetics of l-α-acetylmethadol (LAAM) N-demethylation and dextromethorphan O-demethylation. Drug Metab Dispos, 29: 319–325 (2001).PubMedGoogle Scholar
  22. 22.
    Newton DJ, Wang RW, and Lu AYH. Cytochrome P450 inhibitors: evaluation of specificities in the in vitro metabolism of therapeutic agents by (HLM). Drug Metab Dispos, 23: 154–158 (1995).PubMedGoogle Scholar
  23. 23.
    Ono S, Hatanaka T, Hotta H, Satoh T, Gonzalez FJ, and Tsutsui M. Specificity of substrate and inhibitor probes for cytochrome P450s: evaluation of in vitro metabolism using cDNA-expressed human P450s and (HLM). Xenobiotica, 26: 681–693 (1996).PubMedGoogle Scholar
  24. 24.
    Sai Y, Dai R, Yang TJ, Krausz KW, Gonzalez FJ, Gelboin HV, and Shou M. Assessment of specificity of eight chemical inhibitors using cDNA-expressed cytochromes P450. Xenobiotica, 30: 327–343 (2000).PubMedGoogle Scholar
  25. 25.
    Moody DE, James JL, Clawson GA, and Smuckler EA. Correlations among changes in hepatic microsomal components after intoxication with alkyl halides. Mol Pharmacol, 20: 685–693 (1981).PubMedGoogle Scholar
  26. 26.
    Shimada T, Tsumura F, and Yamazaki H. Prediction of human liver microsomal oxidations of 7-ethoxycoumarin and chlorzoxazone with kinetic parameters of recombinant cytochrome P-450 enzymes. Drug Metab Dispos, 27: 1274–1280 (1999).PubMedGoogle Scholar
  27. 27.
    Neff JA, and Moody DE. Differential N-demethylation of l-α-acetylmethadol (LAAM) and norLAAM by cytochrome P450s 2B6, 2C18, and 3A4. Biochem Biophys Res Commun, 284: 751–756 (2001).PubMedGoogle Scholar
  28. 28.
    Andersson T, Miners JO, Veronese ME, and Birkett DJ. Diazepam metabolism by (HLM) is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms. Br J Clin Pharmacol, 38: 131–137 (1994).PubMedGoogle Scholar
  29. 29.
    Ono S, Hatanaka T, Miyazawa S, Tsutsui M, Aoyama T, Gonzalez FJ, and Satoh H. Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6, 2C19 and the 3A subfamily. Xenobiotica, 26: 1155–1166 (1996).PubMedGoogle Scholar
  30. 30.
    Yang TJ, Shou M, Korzekwa KR, Gonzalez FJ, Gelboin HV, and Yang SK. Role of cDNA-expressed human cytochromes P450 in the metabolism of diazepam. Biochem Pharmacol, 55: 889–896 (1998).PubMedGoogle Scholar
  31. 31.
    Yang TJ, Krausz KW, Sai Y, Gonzalez FJ, and Gelboin HV. Eight inhibitory monoclonal antibodies define the role of individual P-450 s in human liver microsomal diazepam, 7-ethoxycoumarin, and imipramine metabolism. Drug Metab Dispos, 27: 102–109 (1999).PubMedGoogle Scholar
  32. 32.
    Shou MG, Lu T, Krausz KW, Sai Y, Yang TJ, Korzekwa KR, Gonzalez FJ, and Gelboin HV. Use of inhibitory monoclonal antibodies to assess the contribution of cytochromes P450 to human drug metabolism. Eur J Pharmacol, 394: 199–209 (2000).PubMedGoogle Scholar
  33. 33.
    Niwa T, Shiraga T, Ishii I, Kagayama A, and Takagi A. Contribution of human hepatic cytochrome P450 isoforms to the metabolism of psychotropic drugs. Biol Pharm Bull, 28: 1711–1716 (2005).PubMedGoogle Scholar
  34. 34.
    Fabre G, Rahmani R, Placidi M, Combalbert J, Covo J, Cano J-P, Coulange C, Ducros M, and Rampal M. Characterization of midazolam metabolism using hepatic microsomal fractions and hepatocytes in suspension obtained by perfusing whole human livers. Biochem Pharmacol, 37: 4389–4397 (1988).PubMedGoogle Scholar
  35. 35.
    Kronbach T, Mathys D, Umeno M, Gonzalez FJ, and Meyer UA. Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4. Mol Pharmacol, 36: 89–96 (1989).PubMedGoogle Scholar
  36. 36.
    Gorski JC, Hall SD, Vandenbranden M, Wrighton SA, and Jones DR. Regioselective biotransformation of midazolam by members of the human cytochrome p450 3A (CYP3A) subfamily. Biochem Pharmacol, 47: 1643–1653 (1994).PubMedGoogle Scholar
  37. 37.
    Thummel KE, Shen DD, Podoll TD, Kunze KL, Trager WF, Hartwell PS, Raisys VA, Marsh CL, McVicar JP, Barr DM, Perkins JD, and Carithers J, R.L. Use of midazolam as a human cytochrome P450 3 probe: In vitro-in vivo correlations in liver transplant patients. J Pharmacol Exp Ther, 271: 54956 (1994).Google Scholar
  38. 38.
    Wandel C, Bocker R, Bohrer H, Browne A, Rugheimer E, and Martin E. Midazolam is metabolized by at least three different cytochrome P450 enzymes. Br J Anaesth, 73: 658–661 (1994).PubMedGoogle Scholar
  39. 39.
    Wrighton SA, and Ring BJ. Inhibition of human CYP3A catalyzed 1′-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine, and nizatidine. Pharm Res, 11: 921–924 (1994).PubMedGoogle Scholar
  40. 40.
    Ghosal A, Satoh H, Thomas PE, Bush E, and Moore D. Inhibition and kinetics of cytochrome P4503A activity in microsomes from rat, human, and cDNA-expressed human cytochrome P450. Drug Metab Dispos, 24: 940–947 (1996).PubMedGoogle Scholar
  41. 41.
    von Moltke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS, and Shader RI. Midazolam hydroxylation by (HLM) in vitro: Inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents. J Clin Pharmacol, 36: 783–791 (1996).Google Scholar
  42. 42.
    Ekins S, Vandenbranden M, Ring BJ, Gillespie JS, Yang TJ, Gelboin HV, and Wrighton SA. Further characterization of the expression in liver and catalytic activity of CYP2B6. J Pharmacol Exp Ther, 286: 1253–1259 (1998).PubMedGoogle Scholar
  43. 43.
    Wandel C, Bocker RH, Bohrer H, deVries JX, Hofman W, Walter K, Kleingeist B, Neff S, Ding R, Walter-Sack I, and Martin E. Relationship between hepatic cytochrome P450 3A content and activity and the disposition of midazolam administered orally. Drug Metab Dispos, 26: 110–114 (1998).PubMedGoogle Scholar
  44. 44.
    Perloff MD, von Moltke LL, Court MH, Kotegawa T, Shader RI, and Greenblatt DJ. Midazolam and triazolam biotransformation in mouse and (HLM): Relative contribution of CYP3A and CYP2C isoforms. J Pharmacol Exp Ther, 292: 618–628 (2000).PubMedGoogle Scholar
  45. 45.
    Hamaoka N, Oda Y, Hase I, and Asada A. Cytochrome P4502B6 and 2C9 do not metabolize midazolam: kinetic analysis and inhibition study with monoclonal antibodies. Brit J Anaesth, 86: 540–544 (2001).PubMedGoogle Scholar
  46. 46.
    He P, Court MH, Greenblatt DJ, and von Moltke LL. Factors influencing midazolam hydroxylation activity in (HLM). Drug Metab Dispos, 34: 1198–1207 (2006).PubMedGoogle Scholar
  47. 47.
    von Moltke LL, Greenblatt DJ, Harmatz JS, Duan SX, Harrel LM, Cotreau-Bibbo MM, Pritchard GA, Wright CE, and Shader RI. Triazolam biotransformation by (HLM) in vitro: Effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. J Pharmacol Exp Ther, 276: 370–379 (1996).Google Scholar
  48. 48.
    Schmider J, Greenblatt DJ, von Moltke LL, Harmatz JS, Duan SX, Karsov D, and Shader RI. Characterization of six in vitro reactions mediated by human cytochrome P450: application to the testing of cytochrome P450-directed antibodies. Pharmacology, 52: 125–134 (1996).PubMedGoogle Scholar
  49. 49.
    Gorski JC, Jones DR, Hamman MA, Wrighton SA, and Hall SD. Biotransformation of alprazolam by members of the human cytochrome P4503A subfamily. Xenobiotica, 29: 931–944 (1999).PubMedGoogle Scholar
  50. 50.
    Hirota N, Ito K, Iwatsubo T, Green CE, Tyson CA, Shimada N, Suzuki H, and Sugiyama Y. In vitro/in vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humans. Biopharm Drug Dispos, 22: 53–71 (2001).PubMedGoogle Scholar
  51. 51.
    Allqvist A, Miura J, Bertilsson L, and Mirghani RA. Inhibition of CYP3A4 and CYP3A5 catalyzed metabolism of alprazolam and quinine by ketoconazole as racemate and four different enantiomers. Eur J Clin Pharmacol, 63: 173–179 (2007).PubMedGoogle Scholar
  52. 52.
    Venkatakrishnan K, von Moltke LL, Duan SX, Fleishaker JC, Shader RI, and Greenblatt DJ. Kinetic characterization and identification of the enzymes responsible for hepatic biotransformation of adinazolam and N-desmethyladinazolam in man. J Pharm Pharmacol, 50: 265–274 (1997).Google Scholar
  53. 53.
    Coller JK, Somogyi AA, and Bochner F. Flunitrazepam oxidative metabolism in (HLM): involvement of CYP2C19 and CYP3A4. Xenobiotica, 29: 973–986 (1999).PubMedGoogle Scholar
  54. 54.
    Hesse LM, Venkatakrishnan K, von Moltke LL, Shader RI, and Greenblatt DJ. CYP3A4 is the major CYP isoform mediating the in vitro hydroxylation and demethylation of flunitrazepam. Drug Metab Dispos, 29: 133–140 (2001).PubMedGoogle Scholar
  55. 55.
    Kilicarslan T, Haining RL, Rettie AE, Busto U, Tyndale RF, and Sellers EM. Flunitrazepam metabolism by cytochrome P450s 2C19 and 3A4. Drug Metab Dispos, 29: 460–465 (2001).PubMedGoogle Scholar
  56. 56.
    Senda C, Kishimoto W, Sakai K, Nagakura A, and Igarashi T. Identification of human cytochrome P450 isoforms involved in the metabolism of brotizolam. Xenobiotica, 27: 913–922 (1997).PubMedGoogle Scholar
  57. 57.
    Giraud C, Tran A, Rey E, Vincent J, Treluyer JM, and Pons G. In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: Importance of CYP2C19. Drug Metab Dispos, 32: 1279–1286 (2004).PubMedGoogle Scholar
  58. 58.
    Miura M, and Ohkubo T. In vitro metabolism of quazepam in human liver and intestine and assessment of drug interactions. Xenobiotica, 34: 1001–1011 (2004).PubMedGoogle Scholar
  59. 59.
    Miura M, Otani K, and Ohkubo T. Identification of human cytochrome P450 enzymes involved in the formation of 4-hydroxyestazolam from estazolam. Xenobiotica, 35: 455–465 (2005).PubMedGoogle Scholar
  60. 60.
    Shimada T, Yamazaki H, Mimura M, Inui Y, and Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther, 270: 414–423 (1994).PubMedGoogle Scholar
  61. 61.
    Floyd MD, Gervasini G, Masica AL, Mayo G, George AL, Bhat K, Kim RB, and Wilkinson GR. Genotype-phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European- and African-American men and women. Pharmacogenetics, 13: 595–606 (2003).PubMedGoogle Scholar
  62. 62.
    He P, Court MH, Greenblatt DJ, and von Moltke LL. Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin Pharmacol Ther, 77: 373–387 (2005).PubMedGoogle Scholar
  63. 63.
    Perera MA, Thirumaran RK, Cox NJ, Hanauer S, Das S, Brimer-Cline C, Lamba V, Schuetz EG, Ratain MJ, and Di Rienzo A. Prediction of CYP3A4 enzyme activity using haplotype tag SNPs in African Americans. Pharmacogenomics J, 9: 49–60 (2009).PubMedGoogle Scholar
  64. 64.
    Oneda B, S. C, Sirot EJ, Bochud M, Ansermot N, and Eap CB. The P450 oxidoreductase genotype is associated with CYP3A4 activity as measured by the midazolam phenotyping test. Pharmacogenet Genom, 19: 877–883 (2009).Google Scholar
  65. 65.
    Park JY, Kim KA, Park PW, Lee OJ, Kang DK, Shon JH, Liu KH, and Shin JG. Effect of CYP3A5*3 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy subjects. Clin Pharmacol Ther, 79: 590–599 (2006).PubMedGoogle Scholar
  66. 66.
    Bertilsson L, Henthorn TK, Sanz E, Tybring G, Sawe J, and Villen T. Importance of genetic factors in the regulation of diazepam metabolism: Relationship to S-mephenytoin, but not debrisoquin, hydroxylation phenotype. Clin Pharmacol Ther, 45: 348–355 (1989).PubMedGoogle Scholar
  67. 67.
    Sohn D-R, Kusaka T, Shin SG, Jang I-J, Shin JG, and Chiba K. Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics. Clin Pharmacol Ther, 52: 160–169 (1992).PubMedGoogle Scholar
  68. 68.
    Qin Y-P, Xie H-G, Wang W, He N, Huang S-L, Xu Z-H, Ou-Yang D-S, Wang Y-J, and Zhou H-H. Effect of the gene dosage of CYP2C19 on diazepam metabolism in Chinese subjects. Clin Pharmacol Ther, 66: 642–646 (1999).PubMedGoogle Scholar
  69. 69.
    Inomata S, Nagashima A, Itagaki F, Homma M, Nishimura M, Osaka Y, Okuyama KA, Tanaka E, Nakamura T, Kohda Y, Naito S, Miyabe M, and Toyooka H. CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia. Clin Pharmacol Ther, 78: 647–655 (2005).PubMedGoogle Scholar
  70. 70.
    Zhang Y, Reviriego J, Lou Y, Sjoqvist F, and Bertilsson L. Diazepam metabolism in native Chinese poor and extensive hydroxylators of S-mephenytoin: interethnic differences in comparison with white subjects. Clin Pharmacol Ther, 48: 496–502 (1990).PubMedGoogle Scholar
  71. 71.
    Bertilsson L, and Kalow W. Why are diazepam metabolism and polymorphic S-mephenytoin hydroxylation associated with each other in white and Korean populations but not in Chinese populations. Clin Pharmacol Ther, 53: 608–610 (1993).PubMedGoogle Scholar
  72. 72.
    Lennestal R, Lakso HA, Nilsson M, and Mjorndal T. Urine monitoring of diazepam abuse – new intake or not? J Anal Toxicol, 32: 402–407 (2008).PubMedGoogle Scholar
  73. 73.
    Contin M, Sangiorgi S, Riva R, Parmeggiani A, Albani F, and Baruzzi A. Evidence of polymorphic CYP2C19 involvement in the human metabolism of N-desmethylclobazam. Ther Drug Monit, 24: 737–741 (2002).PubMedGoogle Scholar
  74. 74.
    Parmeggiani A, Posar A, Sangiorgi S, and Giovanardi-Rossi P. Unuasual side-effects due to clobazam: a case report with genetic study of CYP2C19. Brain Dev, 26: 63–66 (2003).Google Scholar
  75. 75.
    Seo T, Nagata R, Ishitsu T, Murata T, Takaishi C, Hori M, and Nakagawa K. Impact of CYP2C19 polymorphisms on the efficacy of clobazam therapy. Pharmacogenomics, 9: 527–537 (2008).PubMedGoogle Scholar
  76. 76.
    Fukasawa T, Yasui-Furukori N, Suzuki A, Inoue Y, Tateishi T, and Otani K. Pharmacokinetics and pharmacodynamics of etizolam are influenced by polymorphic CYP2C19 activity. Eur J Clin Pharmacol, 61: 791–795 (2005).PubMedGoogle Scholar
  77. 77.
    Otani K, Yasui N, Kaneko S, Ohkubo T, Osanai T, Sugawara K, Hayashi K, Chiba K, and Ishizaki T. Effects of genetically determined S-mephenytoin 4-hydroxylation status and cigarette smoking on the single-dose pharmacokinetics of oral alprazolam. Neuropsychopharmacology, 16: 8–14 (1997).PubMedGoogle Scholar
  78. 78.
    Yasui N, Otani K, Ohkubo T, Osanai T, Sugawara K, Chiba K, Ishizaki T, and Kaneko S. Single-dose pharmacokinetics and pharmacodynamics of oral triazolam in relation to cytochrome P4502C19 (CYP2C19) activity. Ther Drug Monit, 19: 371–374 (1997).PubMedGoogle Scholar
  79. 79.
    Gafni I, Busto UE, Tyndale RF, Kaplan HL, and Sellers EM. The role of cytochrome P450 2C19 activity in flunitrazepam metabolism in vivo. J Clin Psychopharmacol, 23: 169–175 (2003).PubMedGoogle Scholar
  80. 80.
    Aoshima T, Fukasawa T, Otsuji Y, Okuyama N, Gerstenberg G, Miura M, Ohkubo T, Sugawara K, and Otani K. Effects of the CYP2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam. Prog Neuro-Psych Biol Psych, 27: 535–538 (2003).Google Scholar
  81. 81.
    Abernethy DR, Greenblatt DJ, Ochs HR, and Shader RI. Benzodiazepine drug-drug interactions commonly occurring in clinical practice. Curr Med Res Opin, 8: (Suppl 4) 80–93 (1984).PubMedGoogle Scholar
  82. 82.
    Abernethy DR, Greenblatt DJ, and Shader RI. Benzodiazepine hypnotic metabolism: drug interactions and clinical implications. Acta Psychiatr Scand Suppl 332, 74: 32–38 (1986).PubMedGoogle Scholar
  83. 83.
    Yuan R, Flockhart DA, and Balian JD. Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam. J Clin Pharmacol, 39: 1109–1125 (1999).PubMedGoogle Scholar
  84. 84.
    Sellers EM, and Busto U. Benzodiazepines and ethanol: assessment of the effects and consequences of psychotropic drug interactions. J Clin Psychopharmacol, 2: 249–262 (1982).PubMedGoogle Scholar
  85. 85.
    Chan AWK. Effects of combined alcohol and benzodiazepine: a review. Drug Alcohol Depend, 13: 315–341 (1984).PubMedGoogle Scholar
  86. 86.
    Linnoila MI. Benzodiazepines and alcohol. J Psychiat Res, 24: (Suppl 2) 121–127 (1990).PubMedGoogle Scholar
  87. 87.
    Tanaka E. Toxicological interactions between alcohol and benzodiazepines. Clin Toxicol, 40: 69–75 (2002).Google Scholar
  88. 88.
    Serfaty M, and Masterton G. Fatal poisonings attributed to benzodiazepines in Britain during the 1980 s. Br J Psychiatry, 163: 386–393 (1993).PubMedGoogle Scholar
  89. 89.
    Buckley NA, Dawson AH, Whyte IM, and O’Connell DL. Relative toxicity of benzodiazepines in overdose. Br Med J, 310: 219–221 (1995).Google Scholar
  90. 90.
    Busto U, Kaplan HL, and Sellers EM. Benzodiazepine-associated emergencies in Toronto. Am J Psychiatry, 137: 224–227 (1980).PubMedGoogle Scholar
  91. 91.
    Finkle BS, McCloskey KL, and Goodman LS. Diazepam and drug-associated deaths: a survey in the United States and Canada. J Am Med Assoc, 242: 429–434 (1979).Google Scholar
  92. 92.
    Hojer J, Baehrendtz S, and Gustafsson L. Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period. J Int Med, 226: 117–122 (1989).Google Scholar
  93. 93.
    Richards RG, Reed D, and Cravey RH. Death from intravenously administered narcotics: a study of 114 cases. J Forensic Sci, 21: 467–482 (1976).PubMedGoogle Scholar
  94. 94.
    Monforte JR. Some observations concerning blood morphine concentrations in narcotic addicts. J Forensic Sci, 22: 718–724 (1977).PubMedGoogle Scholar
  95. 95.
    Goldberger BA, Cone EJ, Grant TM, Caplan YH, Levine BS, and Smialek JE. Disposition of heroin and its metabolites in heroin-related deaths. J Anal Toxicol, 18: 22–28 (1994).PubMedGoogle Scholar
  96. 96.
    Walsh SL, Preston KL, Stitzer ML, Cone EJ, and Bigelow GE. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther, 55: 569–580 (1994).PubMedGoogle Scholar
  97. 97.
    Reynaud M, Tracqui A, Petit G, Potard D, and Courty P. Six deaths linked to misuse of buprenorphine-benzodiazepine combinations. Am J Psychiatry, 155: 448–449 (1998).PubMedGoogle Scholar
  98. 98.
    Papworth DP. High dose buprenorphine for postoperative analgesia. Anaesthesia, 38: 163 (1983).PubMedGoogle Scholar
  99. 99.
    Forrest AL. Buprenorphine and lorazepam. Anaesthesia, 38: 598 (1983).PubMedGoogle Scholar
  100. 100.
    Faroqui MH, Cole M, and Curran J. Buprenorphine, benzodiazepines and respiratory depression. Anaesthesia, 38: 1002–1003 (1983).PubMedGoogle Scholar
  101. 101.
    Gueye PN, Borron SW, Risede P, Monier C, Buneaux F, Debray M, and Baud FJ. Buprenorphine and midazolam act in combination to depress respiration in rats. Toxicol Sci, 65: 107–114 (2002).PubMedGoogle Scholar
  102. 102.
    Kilicarslan T, and Sellers EM. Lack of interaction of buprenorphine with flunitrazepam metabolism. Am J Psychiatry, 157: 1164–1166 (2000).PubMedGoogle Scholar
  103. 103.
    Chang Y, and Moody DE. Effect of benzodiazepines on the metabolism of buprenorphine in (HLM). Eur J Clin Pharmacol, 60: 875–881 (2005).PubMedGoogle Scholar
  104. 104.
    Crouch DJ, Birky MM, Gust SW, Rollins DE, Walsh JM, Moulden JV, Quinlan KE, and Beckel RW. The prevalence of drugs and alcohol in fatally injured truck drivers. J Forensic Sci, 38: 1342–1353 (1993).PubMedGoogle Scholar
  105. 105.
    Lund AK, Preusser DF, Blomberg RD, and Williams AF. Drug use by tractor-trailer drivers. J Forensic Sci, 33: 648–661 (1988).PubMedGoogle Scholar
  106. 106.
    Couper FJ, Pemberton M, Jarvis A, Hughes M, and Logan BK. Prevalence of drug use in commercial tractor-trailer drivers. J Forensic Sci, 47: 562–567 (2002).PubMedGoogle Scholar
  107. 107.
    Moody DE, Crouch DJ, Andrenyak DM, Smith RP, Wilkins DG, Hoffman AM, and Rollins DE. Mandatory post-accident drug and alcohol testing for the Federal Railroad Administration: A comparison of results for two consecutive years. NIDA Res Mono, 100: 79–96 (1991).Google Scholar
  108. 108.
    Lundberg GD, White JM, and Hoffman KI. Drugs (other than or in addition to ethyl alcohol) and driving behavior: a collaborative study of the California Association of Toxicologists. J Forensic Sci, 24: 207–215 (1979).PubMedGoogle Scholar
  109. 109.
    Poklis A, MaGinn D, and Barr JL. Drug findings in “driving under the influence of drugs” cases: a problem of illicit drug use. Drug Alcohol Depend, 20: 57–62 (1987).PubMedGoogle Scholar
  110. 110.
    Jonasson U, Jonasson B, Saldeen T, and Thuen F. The prevalence of analgesics containing dextropropoxyphene or codeine in individuals suspected of driving under the influence of drugs. Forensic Sci Int, 112: 163–169 (2000).PubMedGoogle Scholar
  111. 111.
    Logan BK, and Couper FJ. Zolpidem and driving impairment. J Forensic Sci, 46: 105–110 (2001).PubMedGoogle Scholar
  112. 112.
    Preston KL, Griffiths RR, Stitzer ML, Bigelow GE, and Liebson IA. Diazepam and methadone interactions in methadone maintenance. Clin Pharmacol Ther, 36: 534–541 (1984).PubMedGoogle Scholar
  113. 113.
    Preston KL, Griffiths RR, Cone EJ, Darwin WD, and Gorodetzky CW. Diazepam and methadone blood levels following concurrent administration of diazepam and methadone. Drug Alcohol Depend, 18: 195–202 (1986).PubMedGoogle Scholar
  114. 114.
    Abernethy DR, Greenblatt DJ, Morse DS, and Shader RI. Interaction of propoxyphene with diazepam, alprazolam and lorazepam. Br J Clin Pharmacol, 19: 51–57 (1985).PubMedGoogle Scholar
  115. 115.
    Gamble JAS, Kawar P, Dundee JW, Moore J, and Briggs LP. Evaluation of midazolam as an intravenous induction agent. Anaesthesia, 36: 868–873 (1981).PubMedGoogle Scholar
  116. 116.
    Boldy DAR, English JSC, Lang GS, and Hoare AM. Sedation for endoscopy: a comparison between diazepam, and diazepam plus pethidine with naloxone reversal. Br J Anaesth, 56: 1109–1111 (1984).PubMedGoogle Scholar
  117. 117.
    Tverskoy M, Fleyshman G, Ezry J, Bradley EL, and Kissin I. Midazolam-morphine sedative interaction in patients. Anesth Analges, 68: 282–285 (1989).Google Scholar
  118. 118.
    Kanto J, Sjovall S, and Vuori A. Effect of different kinds of premedication on the induction properties of midazolam. Br J Anaesth, 54: 507–511 (1982).PubMedGoogle Scholar
  119. 119.
    Tomicheck RC, Rosow CE, Philbin DM, Moss J, Teplick RS, and Scheider RC. Diazepam-fentanyl interaction-hemodynamic and hormonal effects in coronary artery surgery. Anesth Analg, 62: 881–884 (1983).PubMedGoogle Scholar
  120. 120.
    Dundee JW, Halliday NJ, McMurray TJ, and Harper KW. Pretreatment with opioids: the effect on thiopentone induction requirements and on the onset of action of midazolam. Anaesthesia, 41: 159–161 (1986).PubMedGoogle Scholar
  121. 121.
    Bailey PL, Pace NL, Ashburn MA, Moll JWB, East KA, and Stanley TH. Frequent hypoxemia and apnea after sedation with midazolam and fentanyl. Anesthesiology, 73: 826–830 (1990).PubMedGoogle Scholar
  122. 122.
    Ben-Shlomo I, Abd-El-Khalim H, Ezry J, Zohar S, and Tverskoy M. Midazolam acts synergistically with fentanyl for induction of anaesthesia. Br J Anaesth, 64: 45–47 (1990).PubMedGoogle Scholar
  123. 123.
    Silbert BS, Rosow CE, Keegan CR, Latta WB, Murphy AL, Moss J, and Philbin DM. The effect of diazepam on induction of anesthesia with alfentanyl. Anesth Analg, 65: 71–77 (1986).PubMedGoogle Scholar
  124. 124.
    Vinik HR, Bradley EL, and Kissin I. Midazolam-alfentanyl synergism for anesthetic induction in patients. Anesth Analg, 69: 213–217 (1989).PubMedGoogle Scholar
  125. 125.
    Short TG, Plummer JL, and Chui PT. Hypnotic and anaesthetic interactions between midazolam, propofol and alfentanyl. Br J Anaesth, 69: 162–167 (1992).PubMedGoogle Scholar
  126. 126.
    Hase I, Oda Y, Tanaka K, Mizutani K, Nakamoto T, and Asada A. I.v. fentanyl decreases the clearance of midazolam. Br J Anaesth, 79: 740–743 (1997).PubMedGoogle Scholar
  127. 127.
    Yun CH, Wood M, Wood AJJ, and Guengerich FP. Identification of the pharmacogenetic determinants of alfentanil metabolism: cytochrome P-450 3A4. An explanation of the variable elimination clearance. Anesthesiology, 77: 467–474 (1992).PubMedGoogle Scholar
  128. 128.
    Labroo RB, Thummel KE, Kunze KL, Podoll T, Trager WF, and Kharasch ED. Catalytic role of cytochrome P4503A4 in multiple pathways of alfentanil metabolism. Drug Metab Dispos, 23: 490–496 (1995).PubMedGoogle Scholar
  129. 129.
    Tateishi T, Krivoruk Y, Ueng YF, Wood AJJ, Guengerich FP, and Wood M. Identification of human liver cytochrome p-450 3A4 as the enzyme responsible for fentanyl and sufentanil n-dealkylation. Anesth Analg, 82: 167–172 (1996).PubMedGoogle Scholar
  130. 130.
    Guitton J, Buronfosse T, Desage M, Flinois J-P, Perdrix J-P, Brazier J-L, and Beaune P. Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth, 80: 788–795 (1998).PubMedGoogle Scholar
  131. 131.
    Oda Y, Mizutani K, Hase I, Nakamoto T, Hamaoka N, and Asada A. Fentanyl inhibits metabolism of midazolam: competitive inhibition of CYP3A4 in vitro. Brit J Anaesth, 82: 900–903 (1999).PubMedGoogle Scholar
  132. 132.
    Swift R, Davidson D, Rosen S, Fitz E, and Camara P. Naltrexone effects on diazepam intoxication and pharmacokinetics in humans. Psychopharmacology, 135: 256–262 (1998).PubMedGoogle Scholar
  133. 133.
    Tverskoy M, Fleyshman G, Bradley EL, and Kissin I. Midazolam-thiopental anesthetic interaction in patients. Anesth Analg, 67: 342–345 (1988).PubMedGoogle Scholar
  134. 134.
    Short TG, Galletly DC, and Plummer JL. Hypnotic and anaesthetic action of thiopentone and midazolam alone and in combination. Br J Anaesth, 66: 13–19 (1991).PubMedGoogle Scholar
  135. 135.
    Short TG, and Chui PT. Propofol and midazolam act synergistically in combination. Br J Anaesth, 67: 539–545 (1991).PubMedGoogle Scholar
  136. 136.
    McClune S, McKay AC, Wright PMC, Patterson CC, and Clarke RSJ. Synergistic interaction between midazolam and propofol. Br J Anaesth, 69: 240–245 (1992).PubMedGoogle Scholar
  137. 137.
    Hamaoka N, Oda Y, Hase I, Mizutani K, Nakamoto T, Ishizaki T, and Asada A. Propofol decreases the clearance of midazolam by inhibiting CYP3A4: An in vivo and in vitro stidy. Clin Pharmacol Ther, 66: 110–117 (1999).PubMedGoogle Scholar
  138. 138.
    Miller E, and Park GR. The effect of oxygen on propofol-induced inhibition of microsomal cytochrome P450 3A4. Anaesthesia, 54: 320–322 (1999).PubMedGoogle Scholar
  139. 139.
    Bond A, Silveira JC, and Lader M. Effects of single doses of alprazolam and alcohol alone and in combination on psychological performance. Hum Psychopharmacol, 6: 219–228 (1991).Google Scholar
  140. 140.
    Taeuber K, Badian M, Brettel HF, Royen T, Rupp W, Sittig W, and Uihlein M. Kinetic and dynamic interaction of clobazam and alcohol. Br J Clin Pharmacol, 7: 91 S–97 S (1979).PubMedGoogle Scholar
  141. 141.
    Seppala T, Palva ES, Mattila MJ, Kortilla K, and Shrotriya RC. Tofisopam, a novel 3,4-benzodiazepine: multiple-dose effects on psychomotor skills and memory. Comparison with diazepam and interactions with ethanol. Psychopharmacology, 69: 209–218 (1980).PubMedGoogle Scholar
  142. 142.
    Saario I. Psychomotor skills during subacute treatment with thioridazine and bromazepam, and their combined effects with alcohol. Ann Clin Res, 8: 117–123 (1976).PubMedGoogle Scholar
  143. 143.
    McManus IC, Ankier SI, Norfolk J, Phillips M, and Priest RG. Effects of psychological performance of the benzodiazepine, loprazolam, alone and with alcohol. Br J Clin Pharmacol, 16: 291–300 (1983).PubMedGoogle Scholar
  144. 144.
    Palva ES, and Linnoila M. Effect of active metabolites of chlordiazepoxide and diazepam, alone or in combination with alcohol, on psychomotor skills related to driving. Eur J Clin Pharmacol, 13: 345–350 (1978).PubMedGoogle Scholar
  145. 145.
    Linnoila M, Stapleton JM, Lister R, Moss H, Lane E, Granger A, and Eckardt MJ. Effects of single doses of alprazolam and diazepam, alone and in combination with ethanol, on psychomotor and cognitive performance and on automatic nervous system reactivity in healthy volunteers. Eur J Clin Pharmacol, 39: 21–28 (1990).PubMedGoogle Scholar
  146. 146.
    Linnoila M, and Hakkinen S. Effects of diazepam and codeine, alone and in combination with alcohol, on simulated driving. Clin Pharmacol Ther, 15: 368–373 (1974).PubMedGoogle Scholar
  147. 147.
    Sellers EM, Frecker RC, and Romach MK. Drug metabolism in the elderly: confounding of age, smoking, and ethanol effects. Drug Metab Rev, 14: 225–250 (1983).PubMedGoogle Scholar
  148. 148.
    de la Maza MP, Hirsch S, Petermann M, Suazo M, Ugarte G, and Bunout D. Changes in microsomal activity in alcoholism and obesity. Alcohol Clin Exp Res, 24: 605–610 (2000).PubMedGoogle Scholar
  149. 149.
    Kostrubsky VE, Strom SC, Wood SG, Wrighton SA, Sinclair PR, and Sinclair JF. Ethanol and isopentanol increase CYP3A and CYP2E in primary cultures of human hepatocytes. Arch Biochem Biophys, 322: 516–520 (1995).PubMedGoogle Scholar
  150. 150.
    Scavone JM, Greenblatt DJ, Harmatz JS, and Shader RI. Kinetic and dynamic interaction of brotizolam and ethanol. Br J Clin Pharmacol, 21: 197–204 (1986).PubMedGoogle Scholar
  151. 151.
    Linnoila M, Otterstrom S, and Antilla M. Serum chlordiazepoxide, diazepam and ­thioridazine concentrations after the simultaneous ingestion of alcohol or placebo drink. Ann Clin Res, 6: 4–6 (1974).PubMedGoogle Scholar
  152. 152.
    Dorian P, Sellers EM, Kaplan HL, Hamilton C, Greenblatt DJ, and Abernethy D. Triazolam and ethanol interaction: kinetic and dynamic consequences. Clin Pharmacol Ther, 37: 558–562 (1985).PubMedGoogle Scholar
  153. 153.
    Ochs HR, Greenblatt DJ, Verburg-Ochs B, Harmatz JS, and Grehl H. Disposition of clotiazepam: influence of age, sex, oral contraceptives, cimetidine, isoniazid and ethanol. Eur J Clin Pharmacol, 26: 55–59 (1984).PubMedGoogle Scholar
  154. 154.
    Linnoila M, Erwin CW, Brendle A, and Loque P. Effects of alcohol and flunitrazepam on mood and performance in healthy young men. J Clin Pharmacol, 21: 430–435 (1981).PubMedGoogle Scholar
  155. 155.
    Girre C, Hirschhorn M, Bertaux L, Palombo S, and Fournier PE. Comparison of performance of healthy volunteers given prazepam alone or combined with ethanol. Relation to drug plasma concentrations. Int Clin Psychopharmacol, 6: 227–238 (1991).PubMedGoogle Scholar
  156. 156.
    Hayes SL, Pablo G, Radomoki T, and Palmer RG. Ethanol and oral diazepam absorption. N Engl J Med, 296: 186–189 (1977).PubMedGoogle Scholar
  157. 157.
    Laisi U, Linnoila M, Seppala T, Himberg J-J, and Mattila MJ. Pharmacokinetic and pharmacodynamic interactions of diazepam with different alcoholic beverages. Eur J Clin Pharmacol, 16: 263–270 (1979).Google Scholar
  158. 158.
    Sellers EM, Naranjo CA, Giles HG, Frecker RC, and Beeching M. Intravenous diazepam and oral ethanol interaction. Clin Pharmacol Ther, 28: 638–645 (1980).PubMedGoogle Scholar
  159. 159.
    Morland J, Setekleiv J, Haffner JFW, Stromsaether CE, Danielsen A, and Wethe GH. Combined effects of diazepam and ethanol on mental and psychomotor functions. Acta Pharmacol Toxicol, 34: 5–15 (1974).Google Scholar
  160. 160.
    Greenblatt DJ, Shader RI, Weinberger DR, Allen MD, and MacLaughlin DS. Effect of a cocktail on diazepam absorption. Psychopharmacology, 57: 199–203 (1978).PubMedGoogle Scholar
  161. 161.
    Divoll M, and Greenblatt DJ. Alcohol does not enhance diazepam absorption. Pharmacology, 22: 263–268 (1981).PubMedGoogle Scholar
  162. 162.
    Busby WF, Ackermann JM, and Crespi CL. Effect of methanol, ethanol, dimethyl sulfoxide, and acetonitrile on in vitro activities of cDNA-expressed human cytochromes P-450. Drug Metab Dispos, 27: 246–249 (1999).PubMedGoogle Scholar
  163. 163.
    Perry PJ, Wilding DC, Fowler RC, Helper CD, and Caputo JF. Absorption of oral and intramuscular chlordiazepoxide by alcoholics. Clin Pharmacol Ther, 23: 535–541 (1978).PubMedGoogle Scholar
  164. 164.
    Sellers EM, Greenblatt DJ, Zilm DH, and Degani N. Decline in chlordiazepoxide plasma levels during fixed-dose therapy of alcohol withdrawal. Br J Clin Pharmacol, 6: 370–372 (1978).PubMedGoogle Scholar
  165. 165.
    Sellman R, Pekkarinen A, Kangas L, and Raijola E. Reduced concentrations of plasma diazepam in chronic alcoholic patients following an oral administration of diazepam. Acta Pharmacol Toxicol, 36: 25–32 (1975).Google Scholar
  166. 166.
    Sellman R, Kanto J, Raijola E, and Pekkarinen A. Human and animal study on elimination from plasma and metabolism of diazepam after chronic alcohol intake. Acta Pharmacol Toxicol, 36: 33–38 (1975).Google Scholar
  167. 167.
    Pond SM, Phillips M, Benowitz NL, Galinsky RE, Tong TG, and Becker CE. Diazepam kinetics in acute alcohol withdrawal. Clin Pharmacol Ther, 25: 832–836 (1979).PubMedGoogle Scholar
  168. 168.
    Nair SG, Gamble JAS, Dundee JW, and Howard PJ. The influence of three antacids in the absorption and clinical action of oral diazepam. Br J Anaesth, 48: 1175–1180 (1976).PubMedGoogle Scholar
  169. 169.
    Elliot P, Dundee JW, Elwood RJ, and Collier PS. The influence of H2 receptor antagonists on the plasma concentration of midazolam and temazepam. Eur J Anesth, 1: 245–251 (1984).Google Scholar
  170. 170.
    Greenblatt DJ, Shader RI, Harmatz JS, Franke K, and Koch-Weser J. Influence of magnesium and aluminum hydroxide mixture on chlordiazepoxide absorption. Clin Pharmacol Ther, 19: 234–239 (1976).PubMedGoogle Scholar
  171. 171.
    Chun AHC, Carrigan PJ, Hoffman DJ, Kershner RP, and Stuart JD. Effect of antacids on absorption of clorazepate. Clin Pharmacol Ther, 22: 329–335 (1977).PubMedGoogle Scholar
  172. 172.
    Shader RI, Georgotas A, Greenblatt DJ, Harmatz JS, and Allen MD. Impaired absorption of desmethyldiazepam from clorazepate by magnesium aluminum hydroxide. Clin Pharmacol Ther, 24: 308–315 (1978).PubMedGoogle Scholar
  173. 173.
    Greenblatt DJ, Allen MD, MacLaughlin DS, Harmatz JS, and Shader RI. Diazepam absorption: effect of antacids and food. Clin Pharmacol Ther, 24: 600–609 (1978).PubMedGoogle Scholar
  174. 174.
    Abruzzo CW, Macasieb T, Weinfeld R, Rider AJ, and Kaplan SA. Changes in the oral absorption characteristics in man of dipotassium clorazepate at normal and elevated gastric pH. J Pharmacokinet Biopharm, 5: 377–390 (1977).PubMedGoogle Scholar
  175. 175.
    Shader RI, Ciraulo DA, Greenblatt DJ, and Harmatz JS. Steady-state plasma desmethyldiazepam during long-term clorazepate use: effect of antacids. Clin Pharmacol Ther, 31: 180–183 (1982).PubMedGoogle Scholar
  176. 176.
    Kroboth PD, Smith RB, Rault R, Silver MR, Sorkin MI, Puschett JB, and Juhl RP. Effects of end-stage renal disease and aluminum hydroxide on temazepam kinetics. Clin Pharmacol Ther, 37: 453–459 (1985).PubMedGoogle Scholar
  177. 177.
    Kroboth PD, Smith RB, Silver MR, Rault R, Sorkin MI, Puschett JB, and Juhl RP. Effects of end stage renal disease and aluminium hydroxide on triazolam pharmacokinetics. Br J Clin Pharmacol, 19: 839–842 (1985).PubMedGoogle Scholar
  178. 178.
    Lima DR, Santos RM, Werneck E, and Andrade GN. Effect of orally administered misoprostol and cimetidine on the steady state pharmacokinetics of diazepam and nordiazepam in human volunteers. Eur J Drug Metab Pharmacokinet, 16: 161–170 (1991).PubMedGoogle Scholar
  179. 179.
    Bateman DN. The action of cispride on gastric emptying and the pharmacodynamics and pharmacokinetics of diazepam. Eur J Clin Pharmacol, 30: 205–208 (1986).PubMedGoogle Scholar
  180. 180.
    Dal Negro R. Pharmacokinetic drug interactions with anti-ulcer drugs. Clin Pharmacokinet, 35: 135–150 (1998).Google Scholar
  181. 181.
    Flockhart DA, Desta Z, and Mahal SK. Selection of drugs to treat gastro-oesophageal reflux disease – The role of drug interactions. Clin Pharmacokinet, 39: 295–309 (2000).PubMedGoogle Scholar
  182. 182.
    Knodell RG, Browne DG, Gwozdz GP, Brian WR, and Guengerich FP. Differential inhibition of individual human liver cytochromes P-450 by cimetidine. Gastroenterology, 101: 1680–1691 (1991).PubMedGoogle Scholar
  183. 183.
    Martinez C, Albet C, Agundez JAG, Herrero E, Carrillo JA, Marquez M, Benitez J, and Ortiz JA. Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H2-receptor antagonists. Clin Pharmacol Ther, 65: 369–376 (1999).PubMedGoogle Scholar
  184. 184.
    Klotz U, Arvela P, Pasanen, Kroemer H, and Pelkonen O. Comparative effects of H2-receptor antagonists on drug metabolism in vitro and in vivo. Pharmacol Ther, 33: 157–161 (1987).PubMedGoogle Scholar
  185. 185.
    Hulhoven R, Desager JP, Cox S, and Harvengt C. Influence of repeated administration of cimetidine on the pharmacokinetics and pharmacodynamics of adinazolam in healthy subjects. Eur J Clin Pharmacol, 35: 59–64 (1988).PubMedGoogle Scholar
  186. 186.
    Abernethy DR, Greenblatt DJ, Divoll M, Moschitto LJ, Harmatz JS, and Shader RI. Interaction of cimetidine with triazolobenzodiazepines alprazolam and triazolam. Psychopharmacology, 80: 275–278 (1983).PubMedGoogle Scholar
  187. 187.
    Pourbaix S, Desager JP, Hulhoven R, Smith RB, and Harvengt C. Pharmacokinetic consequences of long term coadministration of cimetidine and triazolobenzodiazepines, alprazolam and triazolam, in healthy subjects. Int J Clin Pharmacol Ther Toxicol, 23: 447–451 (1985).PubMedGoogle Scholar
  188. 188.
    Ochs HR, Greenblatt DJ, Friedman H, Burstein ES, Locniskar A, Harmatz JS, and Shader RI. Bromazepam pharmacokinetics: influence of age, gender, oral contraceptives, cimetidine and propranolol. Clin Pharmacol Ther, 41: 562–570 (1987).PubMedGoogle Scholar
  189. 189.
    Desmond PV, Patwardhan RV, Schenker S, and Speeg KV. Cimetidine impairs elimination of chlordiazepoxide (Librium) in man. Ann Intern Med, 93: 266–268 (1980).PubMedGoogle Scholar
  190. 190.
    Pullar T, Edwards D, Haigh JRM, Peaker S, and Feely MP. The effect of cimetidine on the single dose pharmacokinetics of oral clobazam and N-desmethylclobazam. Br J Clin Pharmacol, 23: 317–321 (1987).PubMedGoogle Scholar
  191. 191.
    Divoll M, Greenblatt DJ, Abernethy DR, and Shader RI. Cimetidine impairs clearance of antipyrine and desmethyldiazepam in the elderly. J Am Geriatr Soc, 30: 684–689 (1982).PubMedGoogle Scholar
  192. 192.
    Klotz U, and Reimann I. Delayed clearance of diazepam due to cimetidine. N Engl J Med, 302: 1012–1014 (1980).PubMedGoogle Scholar
  193. 193.
    Klotz U, and Reimann I. Elevation of steady-state diazepam levels by cimetidine. Clin Pharmacol Ther, 30: 513–517 (1981).PubMedGoogle Scholar
  194. 194.
    Gough PA, Curry SH, Araujo OE, Robinson JD, and Dallman JJ. Influence of cimetidine on oral diazepam elimination with measurement of subsequent cognitive change. Br J Clin Pharmacol, 14: 739–742 (1982).PubMedGoogle Scholar
  195. 195.
    Abernethy DR, Greenblatt DJ, Divoll M, Ameer B, and Shader RI. Differential effect of cimetidine on drug oxidation (antipyrine and diazepam) vs. conjugation (acetaminophen and lorazepam): prevention of acetaminophen toxicity by cimetidine. J Pharmacol Exp Ther, 224: 508–513 (1983).PubMedGoogle Scholar
  196. 196.
    Greenblatt DJ, Abernethy DR, Morse DS, Harmatz JS, and Shader RI. Clinical importance of the interaction of diazepam and cimetidine. N Eng J Med, 310: 1639–1643 (1984).Google Scholar
  197. 197.
    Andersson T, Andren K, Cederberg C, Edvardsson G, Heggelund A, and Lundborg P. Effect of omeprazole and cimetidine on plasma diazepam levels. Eur J Clin Pharmacol, 39: 51–54 (1990).PubMedGoogle Scholar
  198. 198.
    Greenblatt DJ, Abernethy DR, Koepke HH, and Shader RI. Interaction of cimetidine with oxazepam, lorazepam, and flurazepam. J Clin Pharmacol, 24: 187–193 (1984).PubMedGoogle Scholar
  199. 199.
    Fee JPH, Collier PS, Howard PJ, and Dundee JW. Cimetidine and ranitidine increase midazolam bioavailability. Clin Pharmacol Ther, 41: 80–84 (1987).PubMedGoogle Scholar
  200. 200.
    Ochs HR, Greenblatt DJ, Gugler R, Muntefering G, Locniskar A, and Abernethy DR. Cimetidine impairs nitrazepam clearance. Clin Pharmacol Ther, 34: 227–230 (1983).PubMedGoogle Scholar
  201. 201.
    Klotz U, and Reimann I. Influence of cimetidine on the pharmacokinetics of desmethyldiazepam and oxazepam. Eur J Clin Pharmacol, 18: 517–520 (1980).PubMedGoogle Scholar
  202. 202.
    Cox SR, Kroboth PD, Anderson PH, and Smith RB. Mechanism for the interaction between triazolam and cimetidine. Biopharm Drug Dispos, 7: 567–575 (1986).PubMedGoogle Scholar
  203. 203.
    McGowan WAW, and Dundee JW. The effect of intravenous cimetidine on the absorption of orally administered diazepam and lorazepam. Br J Clin Pharmacol, 14: 201–211 (1982).Google Scholar
  204. 204.
    Klotz U, Arvela P, and Rosenkranz B. Effect of single doses of cimetidine and ranitidine on the steady-state plasma levels of midazolam. Clin Pharmacol Ther, 38: 652–655 (1985).PubMedGoogle Scholar
  205. 205.
    Salonen M, Aantaa E, Aaltonen L, and Kanto J. Importance of the interaction of midazolam and cimetidine. Acta Pharmacol Toxicol, 58: 91–95 (1986).Google Scholar
  206. 206.
    Patwardhan RV, Yarborough GW, Desmond PV, Johnson RF, Schenker S, and Speeg KV, Jr. Cimetidine spares the glucuronidation of lorazepam and oxazepam. Gastroenterology, 79: 912–916 (1980).PubMedGoogle Scholar
  207. 207.
    Greenblatt DJ, Abernethy DR, Divoll M, Locniskar A, Harmatz JS, and Shader RI. Noninteraction of temazepam and cimetidine. J Pharm Sci, 73: 399–401 (1984).PubMedGoogle Scholar
  208. 208.
    Klotz U, reimann IW, and Ohnhaus EE. Effect of ranitidine on the steady state pharmacokinetics of diazepam. Eur J Clin Pharmacol, 24: 357–360 (1983).PubMedGoogle Scholar
  209. 209.
    Elwood RJ, Hildebrand PJ, Dundee JW, and Collier PS. Ranitidine influences the uptake of oral midazolam. Br J Clin Pharmacol, 15: 743–745 (1983).PubMedGoogle Scholar
  210. 210.
    Vanderveen RP, Jirak JL, Peters GR, Cox SR, and Bombardt PA. Effect of rantidine on the disposition of orally and intravenously administered triazolam. Clin Pharmacy, 10: 539–543 (1991).Google Scholar
  211. 211.
    Abernethy DR, Greenblatt DJ, Eshelman FN, and Shader RI. Ranitidine does not impair oxidative or conjugative drug metabolism: Noninteraction with antipyrine, diazepam, and lorazepam. Clin Pharmacol Ther, 35: 188–192 (1984).PubMedGoogle Scholar
  212. 212.
    Klotz U, Gottlieb W, Keohane PP, and Dammann HG. Nocturnal doses of ranitidine and nizatidine do not affect the disposition of diazepam. J Clin Pharmacol, 27: 210–212 (1987).PubMedGoogle Scholar
  213. 213.
    Suttle AB, Songer SS, Dukes GE, Hak LJ, Koruda M, Fleishaker JC, and Brouwer KLR. Ranitidine does not alter adinazolam pharmacokinetics or pharmacodynamics. J Clin Psychopharmacol, 12: 282–287 (1992).PubMedGoogle Scholar
  214. 214.
    Klotz U, Arvela P, and Rosenkranz B. Famotidine, a new H2-receptor antagonist, does not affect hepatic elimination of diazepam or tubular secretion of procainamide. Eur J Clin Pharmacol, 28: 671–675 (1985).PubMedGoogle Scholar
  215. 215.
    Locniskar A, Greenblatt DJ, Harmatz JS, Zinny MA, and Shader RI. Interaction of diazepam with famotidine and cimetidine, two H2-receptor antagonists. J Clin Pharmacol, 26: 299–303 (1986).PubMedGoogle Scholar
  216. 216.
    VandenBranden M, Ring BJ, Binkley SN, and Wrighton SA. Interaction of human liver cytochromes P450 in vitro with LY307640, a gastric proton pump inhibitor. Pharmacogenetics, 6: 81–91 (1996).PubMedGoogle Scholar
  217. 217.
    Ko J-W, Sukhova N, Thacker D, Chen P, and Flockhart DA. Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms. Drug Metab Dispos, 25: 853–862 (1997).PubMedGoogle Scholar
  218. 218.
    Tucker GT. The interaction of proton pump inhibitors with cytochromes P450. Aliment Pharmacol Ther, 8: ( Suppl. 1) 33–38 (1994).PubMedGoogle Scholar
  219. 219.
    Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors: focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokinet, 31: 9–28 (1996).PubMedGoogle Scholar
  220. 220.
    Gugler R, and Jensen JC. Omeprazole inhibits oxidative drug metabolism. Gastroenterology, 89: 1235–1241 (1985).PubMedGoogle Scholar
  221. 221.
    Andersson T, Cederberg C, Edvardsson G, Heggelund A, and Lundborg P. Effect of omeprazole treatment on diazepam plasma levels in slow versus normal rapid metabolizers of omeprazole. Clin Pharmacol Ther, 47: 79–85 (1990).PubMedGoogle Scholar
  222. 222.
    Caraco Y, Tateishi T, and Wood AJJ. Interethnic difference in omeprazole’s inhibition of diazepam metabolism. Clin Pharmacol Ther, 58: 62–72 (1995).PubMedGoogle Scholar
  223. 223.
    Lefebvre RA, Flouvat B, Karola-Tamisier S, Moerman E, and Van Ganse E. Influence of lansoprazole treatment on diazepam plasma concentrations. Clin Pharmacol Ther, 52: 458–463 (1992).PubMedGoogle Scholar
  224. 224.
    Gugler R, Hartmann M, Rudi J, Brod I, Huber R, Steinijans VW, Bliesath H, Wurst W, and Klotz U. Lack of pharmacokinetic interaction of pantoprazole with diazepam in man. Br J Clin Pharmacol, 42: 249–252 (1996).PubMedGoogle Scholar
  225. 225.
    Venkatakrishnan K, von Moltke LL, and Greenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism – Clinical relevance. Clin Pharmacokinet, 38: 111–180 (2000).PubMedGoogle Scholar
  226. 226.
    Maurice M, Pichard L, Daujat M, Fabre I, Joyeux H, Domergue J, and Maurel P. Effects of imidazole derivatives on cytochromes P450 from human hepatocytes in primary culture. FASEB J, 6: 752–758 (1992).PubMedGoogle Scholar
  227. 227.
    von Moltke LL, Greenblatt DJ, Duan SX, Harmatz JS, and Shader RI. Inhibition of triazolam hydroxylation by ketoconazole, itraconazole, hydroxyitraconazole and fluconazole in vitro. Pharm Pharmacol Commun, 4: 443–445 (1998).Google Scholar
  228. 228.
    Jurima-Romet M, Crawford K, Cyr T, and Inaba T. Terfenadine metabolism in human liver: in vitro inhibition by macrolide antibiotics and azole antifungals. Drug Metab Dispos, 22: 849–857 (1994).PubMedGoogle Scholar
  229. 229.
    Tassaneeyakul W, Birkett DJ, and Miners JO. Inhibition of human hepatic cytochrome P4502E1 by azole antifungals, CNS-active drugs and non-steroidal anti-inflammatory agents. Xenobiotica, 28: 293–301 (1998).PubMedGoogle Scholar
  230. 230.
    Greenblatt DJ, Wright CE, von Moltke LL, Harmatz JS, Ehrenberg BL, Harrel LM, Corbett K, Counihan M, Tobias S, and Shader RI. Ketoconazole inhibition of triazolam amd alprazolam clearance: Differential kinetic and dynamic consequences. Clin Pharmacol Ther, 64: 237–247 (1998).PubMedGoogle Scholar
  231. 231.
    Schmider J, Brockmoller J, Arold G, Bauer S, and Roots I. Simultaneous assessment of CYP3A4 and CYP1A2 activity in vivo with alprazolam and caffeine. Pharmacogenetics, 9: 725–734 (1999).PubMedGoogle Scholar
  232. 232.
    Brown MW, Maldonado AL, Meredith CG, and Speeg KV. Effect of ketoconazole on hepatic oxidative metabolism. Clin Pharmacol Ther, 37: 290–297 (1985).PubMedGoogle Scholar
  233. 233.
    Olkkola KT, Backman JT, and Neuvonen PJ. Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther, 55: 481–485 (1994).PubMedGoogle Scholar
  234. 234.
    Varhe A, Olkkola KT, and Neuvonen PJ. Oral triazolam is potentially hazardous to patients receiving systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther, 56: 601–607 (1994).PubMedGoogle Scholar
  235. 235.
    Olkkola KT, Ahonen J, and Neuvonen PJ. The effect of systemic antimycotics, itraconazole and fluconazole, on the pharmacokinetics and pharmacodynamics of intravenous and oral midazolam. Anesth Analges, 82: 511–516 (1996).Google Scholar
  236. 236.
    Ahonen J, Olkkola KT, and Neuvonen PJ. Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. Eur J Clin Pharmacol, 51: 415–419 (1997).PubMedGoogle Scholar
  237. 237.
    Varhe A, Olkkola KT, and Neuvonen PJ. Effect of fluconazole dose on the extent of fluconazole-triazolam interaction. Br J Clin Pharmacol, 42: 465–470 (1996).PubMedGoogle Scholar
  238. 238.
    Ohtani Y, Kotegawa T, Tsutsumi K, Morimoto T, Hirose Y, and Nakano S. Effect of fluconazole on the pharmacokinetics and pharmacodynamics of oral and rectal bromazepam: An application of electroencephalography as the pharmacodynamic method. J Clin Pharmacol, 42: 183–191 (2002).PubMedGoogle Scholar
  239. 239.
    Yasui N, Kondo T, Otani K, Furukori H, Kaneko S, Ohkubo T, Nagasaki T, and Sugawara K. Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam. Psychopharmacology, 139: 269–273 (1998).PubMedGoogle Scholar
  240. 240.
    Ahonen J, Olkkola KT, and Neuvonen PJ. The effect of the antimycotic itraconazole on the pharmacokinetics and pharmacodynamics of diazepam. Fund Clin Pharmacol, 10: 314–318 (1996).Google Scholar
  241. 241.
    Ahonen J, Olkkola KT, and Neuvonen PJ. Effect of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers. Br J Clin Pharmacol, 40: 270–272 (1995).PubMedGoogle Scholar
  242. 242.
    Neuvonen PJ, Varhe A, and Olkkola KT. The effect of ingestion time interval on the interaction between itraconazole and triazolam. Clin Pharmacol Ther, 60: 326–331 (1996).PubMedGoogle Scholar
  243. 243.
    Blyden GT, Scavone JM, and Greenblatt DJ. Metronidazole impairs clearance of phenytoin but not of alprazolam or lorazepam. J Clin Pharmacol, 28: 240–245 (1988).PubMedGoogle Scholar
  244. 244.
    Jensen JC, and Gugler R. Interaction between metronidazole and drugs eliminated by oxidative metabolism. Clin Pharmacol Ther, 37: 407–410 (1985).PubMedGoogle Scholar
  245. 245.
    Wang JS, Backman JT, Kivisto KT, and Neuvonen PJ. Effects of metronidazole on midazolam metabolism in vitro and in vivo. Eur J Clin Pharmacol, 56: 555–559 (2000).PubMedGoogle Scholar
  246. 246.
    Varhe A, Olkkola KT, and Neuvonen PJ. Fluconazole, but not terbinafine, enhances the effects of triazolam by inhibiting its metabolism. Br J Clin Pharmacol, 41: 319–323 (1996).PubMedGoogle Scholar
  247. 247.
    Crewe HK, Lennard MS, Tucker GT, Woods FR, and Haddock RE. The effect of selective serotonin re-uptake inhibitors on Cytochrome P4502D6 (CYP2D6) activity in (HLM). Br J Clin Pharmacol, 34: 262–265 (1992).PubMedGoogle Scholar
  248. 248.
    Otton SV, Ball SE, Cheung SW, Inaba T, Rudolph RL, and Sellers EM. Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br J Clin Pharmacol, 41: 149–156 (1996).PubMedGoogle Scholar
  249. 249.
    Schmider J, Greenblatt DJ, von Moltke LL, Harmatz JS, and Shader RI. Inhibition of cytochrome P450 by nefazodone in vitro: studies of dextromethorphan O- and N-demethylation. Br J Clin Pharmacol, 41: 339–343 (1996).PubMedGoogle Scholar
  250. 250.
    Brosen K, and Naranjo CA. Review of the pharmacokinetic and pharmacodynamic interaction studies with citalopram. Eur Neuropsychopharmacol, 11: 275–283 (2001).PubMedGoogle Scholar
  251. 251.
    Schmider J, Greenblatt DJ, von Moltke LL, Karsov D, and Shader RI. Inhibition of CYP2C9 by selective serotonin reuptake inhibitors in vitro: studies of phenytoin p-hydroxylation. Br J Clin Pharmacol, 44: 495–498 (1997).PubMedGoogle Scholar
  252. 252.
    Lasher TA, Fleishaker JC, Steenwyk RC, and Antal EJ. Pharmacokinetic pharmacodynamic evaluation of the combined administration of alprazolam and fluoxetine. Psychopharmacology, 104: 323–327 (1991).PubMedGoogle Scholar
  253. 253.
    Greenblatt DJ, Preskorn SH, Cotreau MM, Horst WD, and Harmatz JS. Fluoxetine impairs clearance of alprazolam but not of clonazepam. Clin Pharmacol Ther, 52: 479–486 (1992).PubMedGoogle Scholar
  254. 254.
    Lemberger L, Rowe H, Bosomworth JC, Tenbarge JB, and Bergstrom RF. The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam. Clin Pharmacol Ther, 43: 412–419 (1988).PubMedGoogle Scholar
  255. 255.
    Wright CE, Lasher-Sisson TA, Steenwyk RC, and Swanson CN. A pharmacokinetic evaluation of the combined administration of triazolam and fluoxetine. Pharmacotherapy, 12: 103–106 (1992).PubMedGoogle Scholar
  256. 256.
    Perucca E, Gatti G, Cipolla G, Spina E, Barel S, Soback S, Gips M, and Bialer M. Inhibition of diazepam metabolism by fluvoxamine: A pharmacokinetic study in normal volunteers. Clin Pharmacol Ther, 56: 471–476 (1994).PubMedGoogle Scholar
  257. 257.
    Kashuba ADM, Nafziger AN, Kearns GL, Leeder JS, Gotschall R, Rocci ML, Kulawy RW, Beck DJ, and Bertino JS. Effect of fluvoxamine therapy on the activities of CYP1A2, CYP2D6, and CYP3A as determined by phenotyping. Clin Pharmacol Ther, 64: 257–268 (1998).PubMedGoogle Scholar
  258. 258.
    Kroboth PD, Folan MM, Lush RM, Chaikin PC, Shukla UA, Barbhaiya R, and Salazar DE. Coadministration of nefazodone and benzodiazepines: I. Pharmacodynamic assessment. J Clin Psychopharmacol, 15: 306–319 (1995).PubMedGoogle Scholar
  259. 259.
    Greene DS, Salazar DE, Dockens RC, Kroboth PD, and Barbhaiya RH. Coadministration of nefazodone and benzodiazepines: III. A pharmacokinetic interaction study with alprazolam. J Clin Psychopharmacol, 15: 399–408 (1995).PubMedGoogle Scholar
  260. 260.
    Barbhaiya RM, Shukla UA, Kroboth PD, and Greene DS. Coadministration of nefazodone and benzodiazepines: II. A pharmacokinetic interaction study with triazolam. J Clin Psychopharmacol, 15: 320–326 (1995).PubMedGoogle Scholar
  261. 261.
    Greene DS, Salazar DE, Dockens RC, Kroboth PD, and Barbhaiya RH. Coadministration of nefazodone and benzodiazepines: IV. A pharmacokinetic interaction study with lorazepam. J Clin Psychopharmacol, 15: 409–416 (1995).PubMedGoogle Scholar
  262. 262.
    Bonate PL, Kroboth PD, Smith RB, Suarez E, and Oo C. Clonazepam and sertraline: Absence of drug interaction in a multiple-dose study. J Clin Psychopharmacol, 20: 19–27 (2000).PubMedGoogle Scholar
  263. 263.
    Gardner MJ, Baris BA, Wilner KD, and Preskorn SH. Effect of sertraline on the pharmacokinetics and protein binding of diazepam in healthy volunteers. Clin Pharmacokinet, 32: (suppl. 1) 43–49 (1997).PubMedGoogle Scholar
  264. 264.
    Amchin J, Zarycranski W, Taylor KP, Albano D, and Klockowski PM. Effect of venlafaxine on the pharmacokinetics of alprazolam. Psychopharmacology Bull, 34: 211–219 (1998).Google Scholar
  265. 265.
    Troy SM, Lucki I, Peirgies AA, Parker VD, Klockowski PM, and chiang ST. Pharmacokinetic and pharmacodynamic evaluation of the potential drug interaction between venlafaxine and diazepam. J Clin Pharmacol, 35: 410–419 (1995).PubMedGoogle Scholar
  266. 266.
    Shenfield GM, and Griffin JM. Clinical pharmacokinetics of contraceptive steroids: an update. Clin Pharmacokinet, 20: 15–37 (1991).PubMedGoogle Scholar
  267. 267.
    Guengerich FP. Oxidation of 17α-ethynylestradiol by human liver cytochrome P–450. Mol Pharmacol, 33: 500–508 (1988).PubMedGoogle Scholar
  268. 268.
    Back DJ, Houlgrave R, Tjia JF, Ward S, and Orme MLE. Effect of the progestogens, gestodene, 3-keto desogestral, levonorgestrel, norethisterone and norgestimate on the oxidation of ethyloestradiol and other substrates by (HLM). J Ster Biochem Mol Biol, 38: 219–225 (1991).Google Scholar
  269. 269.
    Stoehr GP, Kroboth PD, Juhl RP, Wender DB, Phillips JP, and Smith RB. Effect of oral contraceptives on triazolam, temazepam, alprazolam, and lorazepam kinetics. Clin Pharmacol Ther, 36: 683–690 (1984).PubMedGoogle Scholar
  270. 270.
    Roberts RK, Desmond PV, Wilkinson GR, and Schenker S. Disposition of chlordiazepoxide: sex differences and effects of oral contraceptives. Clin Pharmacol Ther, 25: 826–831 (1979).PubMedGoogle Scholar
  271. 271.
    Patwardhan RV, Mitchell MC, Johnson RF, and Schenker S. Differential effects of oral contraceptive steroids on the metabolism of benzodiazepines. Hepatology, 3: 248–253 (1983).PubMedGoogle Scholar
  272. 272.
    Giles HG, Sellers EM, Naranjo CA, Frecker RC, and Greenblatt DJ. Disposition of intravenous diazepam in young men and women. Eur J Clin Pharmacol, 20: 207–213 (1981).PubMedGoogle Scholar
  273. 273.
    Abernethy DR, Greenblatt DJ, Divoll M, Arendt R, Ochs HR, and Shader RI. Impairment of diazepam metabolism by low-dose estrogen containing oral contraceptive steroids. N Engl J Med, 306: 791–792 (1982).PubMedGoogle Scholar
  274. 274.
    Palovaara S, Kivisto KT, Tapanainen P, Manninen P, Neuvonen PJ, and Laine K. Effect of an oral contraceptive preparation containing ethinylestradiol and gestodene on CYP3A4 activity as measured by midazolam 1′-hydroxylation. Brit J Clin Pharmacol, 50: 333–337 (2000).Google Scholar
  275. 275.
    Jochemsen R, Van der Graaff M, Boeijinga JK, and Breimer DD. Influence of sex, menstrual cycle and oral contraception on the disposition of nitrazepam. Br J Clin Pharmacol, 13: 319–324 (1982).PubMedGoogle Scholar
  276. 276.
    Scavone JM, Greenblatt DJ, Locniskar A, and Shader RI. Alprazolam pharmacokinetics in women on low-dose oral contraceptives. J Clin Pharmacol, 28: 454–457 (1988).PubMedGoogle Scholar
  277. 277.
    Holazo AA, Winkler MB, and Patel IH. Effects of age, gender and oral contraceptives on intramuscular midazolam pharmacokinetics. J Clin Pharmacol, 28: 1040–1045 (1988).PubMedGoogle Scholar
  278. 278.
    Belle DJ, Callaghan JT, Gorski JC, Maya JF, Mousa O, Wrighton SA, and Hall SD. The effects of an oral contraceptive containing ethinyloestradiol and norgestrel on CYP3A activity. Br J Clin Pharmacool, 53: 67–74 (2002).Google Scholar
  279. 279.
    Abernethy DR, Greenblatt DJ, Ochs HR, Weyers D, Divoll M, Harmatz JS, and Shader RI. Lorazepam and oxazepam kinetics in women on low-dose oral contraceptives. Clin Pharmacol Ther, 33: 628–632 (1983).PubMedGoogle Scholar
  280. 280.
    Gorski JC, Wang ZQ, Heahner-Daniels BD, Wrighton SA, and Hall SD. The effect of hormone replacement therapy on CYP3A activity. Clin Pharmacol Ther, 68: 412–417 (2000).PubMedGoogle Scholar
  281. 281.
    Kroboth PD, Smith RB, Stoehr GP, and Juhl RP. Pharmacodynamic evaluation of the benzodiazepine-oral contraceptive interaction. Clin Pharmacol Ther, 38: 525–532 (1985).PubMedGoogle Scholar
  282. 282.
    Kroboth PD, and McAuley JW. Progesterone: Does it affect response to drug. Psychopharmacology Bull, 33: 297–301 (1997).Google Scholar
  283. 283.
    Pichard L, Fabre I, Domergue J, Saint Aubert B, Mourad G, and Maurel P. Cyclosporin A drug interactions: screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes. Drug Metab Dispos, 18: 595–606 (1990).PubMedGoogle Scholar
  284. 284.
    Jawad S, and Richens A. Single dose pharmacokinetic study of clobazam in normal volunteers and epileptic patients. Br J Clin Pharmacol, 18: 873–877 (1984).PubMedGoogle Scholar
  285. 285.
    Dhillon S, and Richens A. Pharmacokinetics of diazepam in epileptic patients and normal volunteers following intravenous administration. Br J Clin Pharmacol, 12: 841–844 (1981).PubMedGoogle Scholar
  286. 286.
    Backman JT, Olkkola KT, Ojala M, Laaksovirta H, and Neuvonen PJ. Concentrations and effects of oral midazolam are greatly reduced in patients treated with carbamazepine or phenytoin. Epilepsia, 37: 253–257 (1996).PubMedGoogle Scholar
  287. 287.
    Contin M, Riva R, Albani F, and Baruzzi A. Effect of felbamate on clobazam and its metabolite kinetics in patients with epilepsy. Ther Drug Monit, 21: 604–608 (1999).PubMedGoogle Scholar
  288. 288.
    Wilensky AJ, Levy RH, Troupin AS, Moretti-Ojemann L, and Friel P. Clorazepate kinetics in treated epileptics. Clin Pharmacol Ther, 24: 22–30 (1978).PubMedGoogle Scholar
  289. 289.
    Furukori H, Otani K, Yasui N, Kondo T, Kaneko S, Shimoyama R, Ohkubo T, Nagasaki T, and Sugawara K. Effect of carbamazepine on the single oral dose pharmacokinetics of alprazolam. Neuropsychopharmacology, 18: 364–369 (1998).PubMedGoogle Scholar
  290. 290.
    Levy RH, Lane EA, Guyot M, Brachet-Liermain A, Cenraud B, and Loiseau P. Analysis of parent drug-metabolite relationship in the presence of an inducer: Application to the carbamazepine-clobazam interaction in normal man. Drug Metab Dispos, 11: 286–292 (1983).PubMedGoogle Scholar
  291. 291.
    Lai AA, Levy RH, and Cutler RE. Time-course of interaction between carbamazepine and clonazepam in normal man. Clin Pharmacol Ther, 24: 316–323 (1978).PubMedGoogle Scholar
  292. 292.
    Arana GW, Epstein S, Molloy M, and Greenblatt DJ. Carbamazepine-induced reduction of plasma alprazolam concentrations: a clinical case report. J Clin Psychiatry, 49: 448–449 (1988).PubMedGoogle Scholar
  293. 293.
    Dhillon S, and Richens A. Serum protein binding of diazepam and its displacement by valproic acid in vitor. Br J Clin Pharmacol, 12: 591–592 (1981).PubMedGoogle Scholar
  294. 294.
    Dhillon S, and Richens A. Valproic acid and diazepam interactions in vivo. Br J Clin Pharmacol, 13: 553–560 (1982).PubMedGoogle Scholar
  295. 295.
    Anderson GD, Gidal BE, Kantor ED, and Wilensky AJ. Lorazepam-valproate interaction: Studies in normal subjects and in isolated perfused rat liver. Epilepsia, 35: 221–225 (1994).PubMedGoogle Scholar
  296. 296.
    Samara EE, Granneman RG, Witt GF, and Cavanaugh JH. Effect of valproate on the pharmacokinetics and pharmacodynamics of lorazepam. J Clin Pharmacol, 37: 442–450 (1997).PubMedGoogle Scholar
  297. 297.
    Tija JF, Back DJ, and Breckenridge AM. Calcium channel antagonists and cyclosporin metabolism: in vitro studies with (HLM). Br J Clin Pharmacol, 28: 362–365 (1989).Google Scholar
  298. 298.
    Sutton D, Butler AM, Nadin L, and Murray M. Role of CYP3A4 in human hepatic diltiazem N-demethylation: inhibition of CYP3A4 activity by oxidized diltiazem metabolites. J Pharmacol Exp Ther, 282: 294–300 (1997).PubMedGoogle Scholar
  299. 299.
    Ma B, Prueksaritanont T, and Lin JH. Drug interactions with calcium channel blockers: Possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos, 28: 125–130 (2000).PubMedGoogle Scholar
  300. 300.
    Shaw L, Lennard MS, Tucker GT, Bax NDS, and Woods HF. Irreversible binding and metabolism of propranolol by (HLM) – relationship to polymorphic oxidation. Biochem Pharmacol, 36: 2283–2288 (1987).PubMedGoogle Scholar
  301. 301.
    Ochs HR, Greenblatt DJ, and Verburg-Ochs B. Propranolol interactions with diazepam, lorazepam, and alprazolam. Clin Pharmacol Ther, 36: 451–455 (1984).PubMedGoogle Scholar
  302. 302.
    Hawksworth GM, Betts T, Crowe A, Knight R, Nyemitei-Addo I, Parry K, Petrie JC, Raffle A, and Parsons A. Diazepam / ß-adrenoceptor antagonist interactions. Br J Clin Pharmacol, 17: 69S–76S (1984).PubMedGoogle Scholar
  303. 303.
    Sonne J, Dossing M, Loft S, Olesen KL, Vollmer-Larsen A, Victor MA, Hamberg O, and Thyssen H. Single dose pharmacokinetics and pharmacodynamics of oral oxazepam during concomitant administration of propranolol and labetalol. Br J Clin Pharmacol, 29: 33–37 (1990).PubMedGoogle Scholar
  304. 304.
    Scott AK, Cameron GA, and Hawksworth GM. Interaction of metoprolol with lorazepam and bromazepam. Eur J Clin Pharmacol, 40: 405–409 (1991).PubMedGoogle Scholar
  305. 305.
    Klotz U, and Reimann IW. Pharmacokineitc and pharmacodynamic interaction study of diazepam and metoprolol. Eur J Clin Pharmacol, 26: 223–226 (1984).PubMedGoogle Scholar
  306. 306.
    Ahonen J, Olkkola KT, Salmenpera M, Hynynen M, and Neuvonen PJ. Effect of diltiazem on midazolam and alfentanil disposition in patients undergoing coronary artery bypass grafting. Anesthesia, 85: 1246–1252 (1996).Google Scholar
  307. 307.
    Backman JT, Olkkola KT, Aranko K, Himberg J-J, and Neuvonen PJ. Dose of midazolam should be reduced during diltiazem and verapamil treatments. Br J Clin Pharmacol, 37: 221–225 (1994).PubMedGoogle Scholar
  308. 308.
    Varhe A, Olkkola KT, and Neuvonen PJ. Diltiazem enhances the effects of triazolam by inhibiting its metabolism. Clin Pharmacol Ther, 59: 369–375 (1996).PubMedGoogle Scholar
  309. 309.
    Kosuge K, Nishimoto M, Kimura M, Umemura K, Nakashima M, and Ohashi K. Enhanced effect of triazolam with diltiazem. Br J Clin Pharmac, 43: 367–372 (1997).Google Scholar
  310. 310.
    Backman JT, Wang J-S, Wen X, Kivisto KT, and Neuvonen PJ. Mibefradil but not isradipine substantially elevates the plasma concentrations of the CYP3A4 substrate triazolam. Clin Pharmacol Ther, 66: 401–407 (1999).PubMedGoogle Scholar
  311. 311.
    Venkatesan K. Pharmacokinetic drug interactions with rifampicin. Clin Pharmacokinet, 22: 47–65 (1992).PubMedGoogle Scholar
  312. 312.
    Westphal JF. Macrolide-induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Brit J Clin Pharmacol, 50: 285–295 (2000).Google Scholar
  313. 313.
    Yamazaki H, and Shimada T. Comparative studies of in vitro inhibition of cytochrome P450 3A4-dependent testosterone 6ß-hydroxylation by roxithromycin and its metabolites, troleandomycin, and erythromycin. Drug Metab Dispos, 26: 1053–1057 (1998).PubMedGoogle Scholar
  314. 314.
    Zhao XJ, Koyama E, and Ishizaki T. An in vitro study on the metabolism and possible drug interactions of rokitamycin, a macrolide antibiotic, using (HLM). Drug Metab Dispos, 27: 776–785 (1999).PubMedGoogle Scholar
  315. 315.
    Lindstrom TD, Hanssen BR, and Wrighton SA. Cytochrome P-450 complex formation by dirithromycin and other macrolides in rat and human livers. Antimicrob Agents Chemother, 37: 265–269 (1993).PubMedGoogle Scholar
  316. 316.
    Marre F, de Sousa G, Orloff AM, and Rahmani R. In vitro interaction between cyclosporin A and macrolide antibiotics. Br J Clin Pharmacol, 35: 447–448 (1993).PubMedGoogle Scholar
  317. 317.
    Greenblatt DJ, von Moltke LL, Harmatz JS, Counihan M, Graf JA, Durol ALB, Mertzanis P, Duan SX, Wright CE, and Shader RI. Inhibition of triazolam clearance by macrolide antimicrobial agents: In vitro correlates and dynamic consequences. Clin Pharmacol Ther, 64: 278–285 (1998).PubMedGoogle Scholar
  318. 318.
    Wen X, Wang J-S, Neuvonen PJ, and Backman JT. Isoniazid is a mechanism-based inhibitor of P450 1A2, 2A6, 2C19 and 3A4 isoforms in (HLM). Eur J Clin Pharmacol, 57: 799–804 (2002).PubMedGoogle Scholar
  319. 319.
    Edwards DJ, Bowles SK, Svensson CK, and Rybak MJ. Inhibition of drug metabolism by quinolone antibiotics. Clin Pharmacokinet, 15: 194–204 (1988).PubMedGoogle Scholar
  320. 320.
    Fuhr U, Wolff T, Harder S, Schymanski P, and Staib AH. Quinolone inhibition of cytochrome P-450-dependent caffeine metabolism in (HLM). Drug Metab Disposit, 18: 1005–1010 (1990).Google Scholar
  321. 321.
    Sarkar M, Polk RE, Guzelian PS, Hunt C, and Karnes HT. In vitro effect of fluoroquinolones on theophylline metabolism in (HLM). Antimicrob Agents Chemother, 34: 594–599 (1990).PubMedGoogle Scholar
  322. 322.
    Ochs HR, Greenblatt DJ, Roberts GM, and Dengler HJ. Diazepam interaction with antituberculous drugs. Clin Pharmacol Ther, 29: 671–678 (1981).PubMedGoogle Scholar
  323. 323.
    Ohnhaus EE, Brockmeyer N, Dylewicz P, and Habicht H. The effect of antipyrine and rifampin on the metabolism of diazepam. Clin Pharmacol Ther, 42: 148–156 (1987).PubMedGoogle Scholar
  324. 324.
    Ochs HR, Greenblatt DJ, and Knuchel M. Differential effect of isoniazid on triazolam oxidation and oxazepam conjugation. Br J Clin Pharmacol, 16: 743–746 (1983).PubMedGoogle Scholar
  325. 325.
    Backman JT, Olkkola KT, and Neuvonen PJ. Rifampin drastically reduces plasma concentrations and effects of oral midazolam. Clin Pharmacol Ther, 59: 7–13 (1996).PubMedGoogle Scholar
  326. 326.
    Backman JT, Kivisto KT, Olkkola KT, and Neuvonen PJ. The area under the plasma concentration-time curve for oral midazolam is 400-fold larger during treatment with itraconazole than with rifampicin. Eur J Clin Pharmacol, 54: 53–58 (1998).PubMedGoogle Scholar
  327. 327.
    Brockmeyer NH, Mertins L, Klimek K, Goos M, and Ohnhaus EE. Comparative effects of rifampin and/or probenecid on the pharmacokinetics of temazepam and nitrazepam. Int J Clin Pharmacol Ther Toxicol, 28: 387–393 (1990).PubMedGoogle Scholar
  328. 328.
    Villikka K, Kivisto KT, Backman JT, Olkkola KT, and Neuvonen PJ. Triazolam is ineffective in patients taking rifampin. Clin Pharmacol Ther, 61: 8–14 (1997).PubMedGoogle Scholar
  329. 329.
    Yasui N, Otani K, Kaneko S, Ohkubo T, Osanai T, Sugawara K, Chiba K, and Ishizaki T. A kinetic and dynamic study of oral alprazolam with and without erythromycin in humans: in vivo evidence for the involvement of CYP3A4 in alprazolam metabolism. Clin Pharmacol Ther, 59: 514–519 (1996).PubMedGoogle Scholar
  330. 330.
    Luurila H, Olkkola KT, and Neuvonen PJ. Interaction between erythromycin and the benzodiazepines diazepam and flunitrazepam. Pharmacol Toxicol, 78: 117–122 (1996).PubMedGoogle Scholar
  331. 331.
    Vanakoski J, Mattila MJ, Vainio P, Idanpaan-Heikkila JJ, and Tornwall M. 150 mg fluconazole does not substantially increase the effects of 10 mg midazolam or the plasma midazolam concentrations in healthy subjects. Int J Clin Pharmacol Ther Toxicol, 33: 518–523 (1995).Google Scholar
  332. 332.
    Olkkola KT, Aranko K, Luurila H, Hiller A, Saarnivaara L, Himberg J-J, and Neuvonen PJ. A potentially hazardous interaction between erythromycin and midazolam. Clin Pharmacol Ther, 53: 298–305 (1993).PubMedGoogle Scholar
  333. 333.
    Zimmermann T, Yeates RA, Laufen H, Scharpf F, Leitold M, and Wildfeuer A. Influence of the antibiotics erythromycin and azithromycin on the pharmacokinetics and pharmacdynamics of midazolam. Arsch-Forsch Drug Metab, 46: 213–217 (1996).Google Scholar
  334. 334.
    Phillips JP, Antal EJ, and Smith RB. A pharmacokinetic drug interaction between erythromycin and triazolam. J Clin Psychopharmacol, 6: 297–299 (1986).PubMedGoogle Scholar
  335. 335.
    Luurila H, Olkkola KT, and Neuvonen PJ. Lack of interaction of erythromycin with temazepam. Ther Drug Monit, 16: 548–551 (1994).PubMedGoogle Scholar
  336. 336.
    Warot D, Bergougnan L, Lamiable D, Berlin I, Benison G, Danjou P, and Puech AJ. Troleandomycin-triazolam interaction in healthy volunteers: pharmacokinetic and psychometric evaluation. Eur J Clin Pharmacol, 32: 389–393 (1987).PubMedGoogle Scholar
  337. 337.
    Backman JT, Aranko K, Himberg J-J, and Olkkola KT. A pharmacokinetic interaction between roxithromycin and midazolam. Eur J Clin Pharmacol, 46: 551–555 (1994).PubMedGoogle Scholar
  338. 338.
    Kamali F, Thomas SHL, and Edwards C. The influence of steady-state ciprofloxacin on the pharmacokinetics and pharmacodynamics of a single dose of diazepam. Eur J Clin Pharmacol, 44: 365–367 (1993).PubMedGoogle Scholar
  339. 339.
    Wijnands WJA, Trooster JFG, Teunissen PC, Cats HA, and Vree TB. Ciprofloxacin does not impair the elimination of diazepam in humans. Drug Metab Dispos, 18: 954–957 (1990).PubMedGoogle Scholar
  340. 340.
    Barry M, Mulcahy F, Merry C, Gibbons S, and Back D. Pharmacokinetics and potential interactions amongst antiretroviral agents used to treat patients with HIV infection. Clin Pharmacokinet, 36: 289–304 (1999).PubMedGoogle Scholar
  341. 341.
    Li XL, and Chan WK. Transport, metabolism and elimination mechanisms of anti-HIV agents. Advan Drug Delivery Rev, 39: 81–103 (1999).Google Scholar
  342. 342.
    Tseng AL, and Foisy MM. Significant interactions with new antiretrovirals and psychotic drugs. Ann Pharmacother, 33: 461–473 (1999).PubMedGoogle Scholar
  343. 343.
    Eagling VA, Back DJ, and Barry MG. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol, 44: 190–194 (1997).PubMedGoogle Scholar
  344. 344.
    Inaba T, Fischer NE, Riddick DS, Stewart DJ, and Hidaka T. HIV protease inhibitors, saquinavir, indinavir and ritonavir: inhibition of CYP3A4-mediated metabolism of testosterone and benzoxazinorifamycin, KRM-1648, in (HLM). Toxicol Lett, 93: 215–219 (1997).PubMedGoogle Scholar
  345. 345.
    Lillibridge JH, Liang BH, Kerr BM, Webber S, Quart B, Shetty BV, and Lee CA. Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate. Drug Metab Dispos, 26: 609–616 (1998).PubMedGoogle Scholar
  346. 346.
    von Moltke LL, Greenblatt DJ, Grassi JM, Granda BW, Duan SX, Fogelman SM, Daily JP, Harmatz JS, and Shader RI. Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. J Clin Pharmacol, 38: 106–111 (1998).Google Scholar
  347. 347.
    Decker CJ, Laitinen LM, Bridson GW, Raybuck SA, Tung RD, and Chaturvedi PR. Metabolism of amprenavir in liver microsomes: role of CYP3A4 inhibition for drug interactions. J Pharm Sci, 87: 803–807 (1998).PubMedGoogle Scholar
  348. 348.
    Zalma A, von Moltke LL, Granda BW, Harmatz JS, Shader RI, and Greenblatt DJ. In vitro metabolism of trazodone by CYP3A: Inhibition by ketoconazole and human immunodeficiency viral protease inhibitors. Biol Psychiat, 47: 655–661 (2000).PubMedGoogle Scholar
  349. 349.
    von Moltke LL, Greenblatt DJ, Granda BW, Giancarlo GM, Duan SX, Daily JP, Harmatz JS, and Shader RI. Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. J Clin Pharmacol, 41: 85–91 (2001).Google Scholar
  350. 350.
    Greenblatt DJ, von Moltke LL, Harmatz JS, Durol ALB, Daily JP, Graf JA, Mertzanis P, Hoffman JL, and Shader RI. Differential impairment of triazolam and zolpidem clearance by ritonavir. J Acq Immune Defic Syndr, 24: 129–136 (2000).Google Scholar
  351. 351.
    Greenblatt DJ, von Moltke LL, Harmatz JS, Durol ALB, Daily JP, Graf JA, Mertzanis P, Hoffman JL, and Shader RI. Alprazolam-ritonavir interaction: implications for product labeling. Clin Pharmacol Ther, 67: 335–341 (2000).PubMedGoogle Scholar
  352. 352.
    Palkama VJ, Ahonen J, Neuvonen PJ, and Olkkola KT. Effect of saquinavir on the pharmacokinetics and pharmacodynamics of oral and intravenoud midazolam. Clin Pharmacol Ther, 66: 33–39 (1999).PubMedGoogle Scholar
  353. 353.
    Yeh RF, Gaver VE, Patterson KB, Rezk NL, Baxter-Meheux F, Blake MJ, Eron JJ, Klein CE, Rublein JC, and Kashuba ADM. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Defic Syndr, 42: 52–60 (2006).PubMedGoogle Scholar
  354. 354.
    Fellay J, Marzolini C, Decosterd L, Golay KP, Baumann P, Buclin T, Telenti A, and Eap CB. Variations of CYP3A activity induced by antiretroviral treatment in HIV-1 infected patients. Eur J Clin Pharmacol, 60: 865–873 (2005).PubMedGoogle Scholar
  355. 355.
    Abel S, Russell D, Whitlock LA, Ridgway CE, and Muirhead GJ. Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/zidovudine, and ethinyloestradiol/levonorgestrel in healthy volunteers. Br J Clin Pharmacol, 65: 19–26 (2008).PubMedGoogle Scholar
  356. 356.
    Nyunt MM, Becker S, Macfarland RT, Chee P, Scarborough R, Everts S, Calandra GB, and Hendrix CW. Pharmacokinetic effect of AMD070, an oral CXCR4 antagonist, on CYP3A4 and CYP2D6 substrates midazolam and dextromethorphan in healthy volunteers. JAIDS, 47: 559–565 (2008).PubMedGoogle Scholar
  357. 357.
    Mathias AA, West S, Hui J, and Kearney BP. Dose-response of ritonavir on hepatic CYP3A activity and elvitegravir oral exposure. Clin Pharmacol Ther, 85: 64–70 (2009).PubMedGoogle Scholar
  358. 358.
    Bailey DG, Spence JD, Munoz C, and Arnold JMO. Interaction of citrus juices with felodipine and nifedipine. Lancet, 337: 268–269 (1991).PubMedGoogle Scholar
  359. 359.
    Watkins PB, Wrighton SA, Schuetz EG, Molowa DT, and Guzelian PS. Identification of glucocortisol-inducible cytochrome P-450 in the intestinal mucosa of rats and man. J Clin Invest, 80: 1029–1036 (1987).PubMedGoogle Scholar
  360. 360.
    Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C, and Watkins PB. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest, 90: 1871–1878 (1992).PubMedGoogle Scholar
  361. 361.
    Bailey DG, Malcolm J, Arnold O, and Spence JD. Grapefruit juice-drug interactions. Br J Clin Pharmacol, 46: 101–110 (1998).PubMedGoogle Scholar
  362. 362.
    Greenblatt DJ, Patki KC, von Moltke LL, and Shader RI. Drug interactions with grapefruit juice: an update. J Clin Psychopharmacol, 21: 357–359 (2001).PubMedGoogle Scholar
  363. 363.
    Lown KS, Bailey DG, Fontana RJ, Janardan SK, Adair CH, Fortlage LA, Brown MB, Guo W, and Watkins PB. Grapefruit juice increases felodipine oral bioavailability in humans by decreasing intestinal CYP 3A protein expression. J Clin Invest, 99: 1–9 (1997).Google Scholar
  364. 364.
    Schmiedlin-Ren P, Edwards DJ, Fitzsimmons ME, He K, Lown KS, Woster PM, Rahman A, Thummel KE, Fisher JM, Hollenberg PF, and Watkins PB. Mechanisms of enhanced oral availability of CYP3A substrates by grapefruit constituents: decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins. Drug Metab Dispos, 25: 1228–1233 (1997).PubMedGoogle Scholar
  365. 365.
    Guengerich FP, and Kim D-H. In vitro inhibition of dihydropyridine oxidation and aflatoxin B1 activation in (HLM) by naringenin and other flavonoids. Carcinogenesis, 11: 2275–2279 (1990).PubMedGoogle Scholar
  366. 366.
    Miniscalco A, Lundahl J, Regardh CG, Edgar B, and Eriksson UG. Inhibition of dihydropyridine metabolism in rat and (HLM) by flavonoids found in grapefruit juice. J Pharmacol Exp Ther, 261: 1195–1199 (1991).Google Scholar
  367. 367.
    Ha HR, Chen J, Leuenberger PM, Freiburghaus AU, and Follath F. In vitro inhibition of midazolam and quinidine metabolism by flavonoids. Eur J Clin Pharmacol, 48: 367–371 (1995).PubMedGoogle Scholar
  368. 368.
    Schubert W, Eriksson U, Edgar B, Cullberg G, and Hedner T. Flavonoids in grapefruit juice inhibit the in vitro hepatic metabolism of 17 beta-estradiol. Eur J Drug Metab Pharmacokinet, 20: 219–224 (1995).PubMedGoogle Scholar
  369. 369.
    Eagling VA, Profit L, and Back DJ. Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-I protease inhibitor saquinavir by grapefruit juice components. Br J Clin Pharmacol, 48: 543–552 (1999).PubMedGoogle Scholar
  370. 370.
    Rashid J, McKinstry C, Renwick AG, Dirnhuber M, Waller DG, and George CF. Quercetin, an in vitro inhibitor of CYP3A, does not contribute to the interaction between nifedipine and grapefruit juice. Br J Clin Pharmacol, 36: 460–463 (1993).PubMedGoogle Scholar
  371. 371.
    Bailey DG, Arnold JMO, Munoz C, and Spence JD. Grapefruit juice-felodipine interaction – mechanism, predictability, and effect of naringin. Clin Pharmacol Ther, 53: 637–642 (1993).PubMedGoogle Scholar
  372. 372.
    Edwards DJ, Bellevue FH, and Woster PM. Identification of 6′,7′-dihydroxybergamottin, a cytochrome P-450 inhibitor in grapefruit juice. Drug Metab Dispos, 24: 1287–1290 (1996).PubMedGoogle Scholar
  373. 373.
    Fukuda K, Ohta T, and Yamazoe Y. Grapefruit component interacting with rat and human P450 CYP3A: possible involvement of non-flavonoid components in drug interaction. Biol Pharm Bull, 20: 560–564 (1997).PubMedGoogle Scholar
  374. 374.
    Fukuda K, Ohta T, Oshima Y, Ohashi N, Yoshikawa M, and Yamazoe Y. Specific CYP3A4 inhibitors in grapefruit juice: furocoumarins dimers as components of drug interaction. Pharmacogenetics, 7: 391–396 (1997).PubMedGoogle Scholar
  375. 375.
    Guo L-Q, Fukuda K, Ohta T, and Yamazoe Y. Role of furanocoumarin derivatives on grapefruit juice-mediated inhibition of human CYP3A activity. Drug Metab Dispos, 28: 766–771 (2000).PubMedGoogle Scholar
  376. 376.
    He K, Iyer KR, Hayes RN, Sinz MW, Woolf TF, and Hollenberg PF. Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice. Chem Res Toxicol, 11: 252–259 (1998).PubMedGoogle Scholar
  377. 377.
    Fuhr U, Klittich K, and Staib AH. Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man. Br J Clin Pharmacol, 35: 431–436 (1993).PubMedGoogle Scholar
  378. 378.
    Edwards DJ, Fitzsimmons ME, Schuetz EG, Yasuda K, Ducharme MP, Warbasse LH, Woster PM, Schuetz JD, and Watkins P. 6 ′,7 ′-Dihydroxybergamottin in grapefruit juice and Seville orange juice: Effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin Pharmacol Ther, 65: 237–244 (1999).PubMedGoogle Scholar
  379. 379.
    Soldner A, Christians U, Susanto M, Wacher VJ, Silverman JA, and Benet LZ. Grapefruit juice activates P-glycoprotein-mediated drug transport. Pharm Res, 16: 478–485 (1999).PubMedGoogle Scholar
  380. 380.
    Kupferschmidt HHT, Ha HR, Ziegler WH, Meier PJ, and Krahenbuhl S. Interaction between grapefruit juice and midazolam in humans. Clin Pharmacol Ther, 58: 20–28 (1995).PubMedGoogle Scholar
  381. 381.
    Andersen V, Pedersen N, Larsen N-E, Sonne J, and Larsen S. Intestinal first pass metabolism of midazolam in kiver cirrhosis – effect of grapefruit juice. Br J Clin Pharmacol, 54: 120–124 (2002).PubMedGoogle Scholar
  382. 382.
    Hukkinen SK, Varhe A, Olkkola KT, and Neuvonen PJ. Plasma concentrations of triazolam are increased by concomitant ingestion of grapefruit juice. Clin Pharmacol Ther, 58: 127–131 (1995).PubMedGoogle Scholar
  383. 383.
    Yasui N, Kondo T, Furukori H, Kaneko S, Ohkubo T, Uno T, Osanai T, Sugawara K, and Otani K. Effects of repeated ingestion of grapefruit juice on the single and multiple oral-dose pharmacokinetics and pharmacodynamics of alprazolam. Psychopharmacology, 150: 185–190 (2000).PubMedGoogle Scholar
  384. 384.
    Vanakoski J, Mattila MJ, and Seppala T. Grapefruit juice does not enhance the effects of midazolam and triazolam in man. Eur J Clin Pharmacol, 50: 501–508 (1996).PubMedGoogle Scholar
  385. 385.
    Backman JT, Maenpaa J, Belle DJ, Wrighton SA, Kivisto KT, and Neuvonen PJ. Lack of correlation between in vitro and in vivo studies on the effects of tangeretin and tangerine juice on midazolam hydroxylation. Clin Pharmacol Ther, 67: 382–390 (2000).PubMedGoogle Scholar
  386. 386.
    Henauer SA, Hollister LE, Gillespie HK, and Moore F. Theophylline antagonizes diazepam-induced psychomotor impairment. Eur J Clin Pharmacol, 25: 743–747 (1983).PubMedGoogle Scholar
  387. 387.
    Tuncok Y, Akpinar O, Guven H, and Akkoclu A. The effects of theophylline on serum alprazolam levels. Int J Clin Pharmacol Ther, 32: 642–645 (1994).PubMedGoogle Scholar
  388. 388.
    Ghoneim MM, Hinrichs JV, Chiang C-K, and Loke WH. Pharmacokinetic and pharmacodynamic interactions between caffeine and diazepam. J Clin Psychopharmacol, 6: 75–80 (1986).PubMedGoogle Scholar
  389. 389.
    Ohnhaus EE, Park BK, Colombo JP, and Heizmann P. The effect of enzyme induction on diazepam metabolism in man. Br J Clin Pharmacol, 8: 557–563 (1979).PubMedGoogle Scholar
  390. 390.
    MacLeod SM, Sellers EM, Giles HG, Billings BJ, Martin PR, Greenblatt DJ, and Marshman JA. Interaction of disulfiram with benzodiazepines. Clin Pharmacol Ther, 24: 583–589 (1978).PubMedGoogle Scholar
  391. 391.
    Diquet B, Gujadhur L, Lamiable D, Warot D, Hayoun H, and Choisy H. Lack of interaction between disulfiram and alprazolam. Eur J Clin Pharmacol, 38: 157–160 (1990).PubMedGoogle Scholar
  392. 392.
    Nakajima M, Suzuki T, Sasaki T, Yokoi T, Hosoyamada A, Yamamoto T, and Kuroiwa Y. Effects of chronic administration of glucocorticoid on midazolam pharmacokinetics in humans. Ther Drug Monit, 21: 507–513 (1999).PubMedGoogle Scholar
  393. 393.
    Villikka K, Kivisto KT, and Neuvonen PJ. The effect of dexamethasone on the pharmacokinetics of triazolam. Pharmacol Toxicol, 83: 135–138 (1998).PubMedGoogle Scholar
  394. 394.
    Mulley BA, Potter BI, Rye RM, and Takeshita K. Interactions between diazepam and paracetamol. J Clin Pharmacy, 3: 25–35 (1978).Google Scholar
  395. 395.
    Abernethy DR, Greenblatt DJ, Ameer B, and Shader RI. Probenecid impairment of acetaminophen and lorazepam clearance: Direct inhibition of ether glucuronide formation. J Pharmacol Exp Ther, 234: 345–349 (1985).PubMedGoogle Scholar
  396. 396.
    Golden PL, Warner PE, Fleishaker JC, Jewell RC, Millikin S, Lyon J, and Brouwer KLR. Effects of probenecid on the pharmacokinetics and pharmacodynamics of adinazolam in humans. Clin Pharmacol Ther, 56: 133–141 (1994).PubMedGoogle Scholar
  397. 397.
    Robertson P, Decory HH, Madan A, and Parkinson A. In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil. Drug Metab Dispos, 28: 664–671 (2000).PubMedGoogle Scholar
  398. 398.
    Robertson P, Hellriegel ET, Arora S, and Nelson M. Effect of modafinal on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers. Clin Pharmacol Ther, 71: 46–56 (2002).PubMedGoogle Scholar
  399. 399.
    Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Cui Y, and Ang CYW. Cytochrome P450 phenotype ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther, 72: 276–287 (2002).PubMedGoogle Scholar
  400. 400.
    Klee H, Faugier J, Hayes C, Boulton T, and Morris J. AIDS-related risk behavior, polydrug use and temazepam. Br J Addict, 85: 1125–1132 (1990).PubMedGoogle Scholar
  401. 401.
    Navaratnam V, and Foong K. Adjunctive drug use among opiate addicts. Curr Med Res Opin, 11: 611–619 (1990).PubMedGoogle Scholar
  402. 402.
    Metzger D, Woody G, De Philippis D, McLellan AT, O’Brien CP, and Platt JJ. Risk factors for needle sharing among methadone-treated patients. Am J Psychiatry, 148: 636–640 (1991).PubMedGoogle Scholar
  403. 403.
    Darke S, Hall W, Ross M, and Wodak A. Benzodiazepine use and HIV risk-taking behaviour among injecting drug users. Drug Alcohol Depend, 31: 31–36 (1992).PubMedGoogle Scholar
  404. 404.
    Barnas C, Rossmann M, Roessler H, Riemer Y, and Fleishchhacker WW. Benzodiazepines and other psychotropic drugs abused by patients in a methadone maintenance program: familiarity and preferance. J Clin Psychopharmacol, 12: 397–402 (1992).PubMedGoogle Scholar
  405. 405.
    Hall W, Bell J, and Carless J. Crime and drug use among applicants for methadone maintenance. Drug Alcohol Depend, 31: 123–129 (1993).PubMedGoogle Scholar
  406. 406.
    San L, Tato J, Torrens M, Castillo C, Farre M, and Cami J. Flunitrazepam consumption among heroin addicts admitted for in-patient detoxification. Drug Alcohol Depend, 32: 281–286 (1993).PubMedGoogle Scholar
  407. 407.
    Darke S, Swift W, Hall W, and Ross M. Drug use, HIV risk-taking and psychosocial correlates of benzodiazepine use among methadone maintenance clients. Drug Alcohol Depend, 34: 67–70 (1993).Google Scholar
  408. 408.
    Strang J, Griffiths P, Abbey J, and Gossop M. Survey of injected benzodiazepines among drug users in Britain. BMJ, 308: 1082 (1994).PubMedGoogle Scholar
  409. 409.
    Garriott JC, DiMaio VJM, Zumwalt RE, and Petty CS. Incidence of drugs and alcohol in fatally injured motor vehicle drivers. J Forensic Sci, 22: 383–389 (1977).PubMedGoogle Scholar
  410. 410.
    Warren R, Simpson H, Hilchie J, Cimbura G, Lucas D, and Bennett R. Drugs detected in fatally injured drivers in the province of Ontario. Alcohol Drugs Traffic Safety, 1: 203–217 (1980).Google Scholar
  411. 411.
    Fortenberry JC, Brown DB, and Shelvin LT. Analysis of drug involvement in traffic fatalities in Alabama. Am J Drug Alcohol Abuse, 12: 257–267 (1986).PubMedGoogle Scholar
  412. 412.
    McLean S, Parsons RS, Chesterman RB, Johnson MG, and Davies NW. Drugs, alcohol and road accidents in Tasmania. Med J Aust, 147: 6–11 (1987).PubMedGoogle Scholar
  413. 413.
    Logan BK, and Schwilke EW. Drug and alcohol use in fatally injured drivers in Washington state. J Forensic Sci, 41: 505–510 (1996).PubMedGoogle Scholar
  414. 414.
    Finkle BS, Biasotti AA, and Bradford LW. The occurrence of some drugs and toxic agents encountered in drinking driver investigations. J Forensic Sci, 13: 236–245 (1968).PubMedGoogle Scholar
  415. 415.
    Robinson TA. The incidence of drugs in impaired driving specimens in Northern Ireland. J Forensic Sci Soc, 19: 237–241 (1979).PubMedGoogle Scholar
  416. 416.
    White JM, Clardy DO, Graves MH, Kuo MC, MacDonald BJ, Wiersema SJ, and Fitzpatrick G. Testing for sedative-hypnotic drugs in the impaired driver: a survey of 72,000 arrests. Clin Toxicol, 18: 945–957 (1981).PubMedGoogle Scholar
  417. 417.
    Peel HW, Perrigo BJ, and Mikhael NZ. Detection of drugs in saliva of impaired drivers. J Forensic Sci, 29: 185–189 (1984).PubMedGoogle Scholar
  418. 418.
    Barbone F, McMahon AD, Davey PG, Morris AD, Reid IC, McDevitt DG, and MacDonald TM. Association of road-traffic accidents with benzodiazepine use. Lancet, 352: 1331–1336 (1998).PubMedGoogle Scholar
  419. 419.
    Liljequist R, Linnoila M, Mattila MJ, Saario I, and Seppala T. Effect of two weeks’ treatment with thioridazine, chlorpromazine, sulpiride and bromazepam, alone or in combination with alcohol, on learning and memory in man. Psychopharmacologia, 44: 205–208 (1975).PubMedGoogle Scholar
  420. 420.
    Hughes FW, Forney RB, and Richards AB. Comparative effect in human subjects of chlordiazepoxide, diazepam, and placebo on mental and physical performance. Clin Pharmacol Ther, 6: 139–145 (1965).PubMedGoogle Scholar
  421. 421.
    Staak M, Raff G, and Strohm H. Pharmacopsychological investigation of changes in mood induced by dipotassium chlorazepate with and without simultaneous alcohol administration. Int J Clin Pharmacol Ther Toxicol, 18: 283–291 (1980).PubMedGoogle Scholar
  422. 422.
    Lawton MP, and Cahn B. The effects of diazepam (Valium®) and alcohol on psychomotor performance. J Nerv Ment Dis, 136: 550–554 (1963).Google Scholar
  423. 423.
    Molander L, and Duvhok C. Acute effects of oxazepam, diazepam and methylperone, alone and in combination with alcohol on sedation, coordination and mood. Acta Pharmacol Toxicol, 38: 145–160 (1976).Google Scholar
  424. 424.
    van Steveninck AL, Gieschke R, Schoemaker RC, Roncari G, Tuk B, Pieters MSM, Breimer DD, and Cohen AF. Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol. Br J Clin Pharmacol, 41: 565–573 (1996).PubMedGoogle Scholar
  425. 425.
    van Steveninck AL, Gieschke R, Schoemaker HC, Pieters MSM, Kroon JM, Breimer DD, and Cohen AF. Pharmacodynamic interactions of diazepam and intravenous alcohol at pseudo steady state. Psychopharmacology, 110: 471–478 (1993).PubMedGoogle Scholar
  426. 426.
    Saario I, and Linnoila M. Effect of subacute treatment with hypnotics, alone or in combination with alcohol, on psychomotor skills related to driving. Acta Pharmacol Toxicol, 38: 382–392 (1976).Google Scholar
  427. 427.
    Lichter JL, Korttila K, Apfelbaum J, Rupani G, Ostman P, Lane B, Hendren M, Dohrn C, Kemen M, and Villalabos T. Alcohol after midazolam sedation: does it really matter. Anesth Analges, 70: S 237 (1990).Google Scholar
  428. 428.
    Saario I, Linnoila M, and Maki M. Interaction of drugs with alcohol on human psychomotor skills related to driving: effect of sleep deprivation or two weeks’ treatment with hypnotics. J Clin Pharmacol, 15: 52–59 (1975).Google Scholar
  429. 429.
    Grigoleit HG, Hajdu P, Hundt HKL, Koeppen D, Malerczyk V, Meyer BH, Muller FO, and Witte PU. Pharmacokinetic aspects of the interaction between clobazam and cimetidine. Eur J Clin Pharmacol, 25: 139–142 (1983).PubMedGoogle Scholar
  430. 430.
    Sanders LD, Whitehead C, Gildersleve CD, Rosen M, and Robinson JO. Interaction of H2-receptor antagonists and benzodiazepine sedation: a double-blind placebo-controlled investigation of the effects of cimetidine and rantidine on recovery after intravenous midazolam. Anaesthesia, 48: 286–292 (1993).PubMedGoogle Scholar
  431. 431.
    Wilson CM, Robinson FP, Thompson EM, Dundee JW, and Elliot P. Effect of pretreatment with ranitidine on the hypnotic action of single doses of midazolam, temazepam and zopiclone. Br J Anaesth, 58: 483–486 (1986).PubMedGoogle Scholar
  432. 432.
    Van Hecken AM, Tjandramaga TB, Verbesselt R, and De Schepper PJ. The influence of diflunisal on the pharmacokinetics of oxazepam. Br J Clin Pharmacol, 20: 225–234 (1985).PubMedGoogle Scholar
  433. 433.
    Huang W, and Moody DE. Immunoassay detection of benzodiazepines and benzodiazepine metabolites in blood. J Anal Toxicol, 19: 333–342 (1995).PubMedGoogle Scholar
  434. 434.
    Back DJ, Tjia JF, Karbwang J, and Colbert J. In vitro inhibition studies of tolbutamide hydroxylase activity of (HLM) by azoles, sulphonamides and quinilines. Br J Clin Pharmacol, 26: 23–29 (1988).PubMedGoogle Scholar
  435. 435.
    Erickson DA, Mather G, Trager WF, Levy RH, and Keirns JJ. Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos, 27: 1488–1495 (1999).PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Center for Human Toxicology, Department of Pharmacology and ToxicologyUniversity of UtahSalt Lake CityUSA

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