Clinical Pharmacokinetics

, Volume 35, Issue 5, pp 361–390 | Cite as

Inhibition and Induction of Cytochrome P450 and the Clinical Implications

  • Jiunn H. LinEmail author
  • Anthony Y. H. Lu
Review Articles Concepts


The cytochrome P450s (CYPs) constitute a superfamily of isoforms that play an important role in the oxidative metabolism of drugs. Each CYP isoform possesses a characteristic broad spectrum of catalytic activities of substrates. Whenever 2 or more drugs are administered concurrently, the possibility of drug interactions exists. The ability of a single CYP to metabolise multiple substrates is responsible for a large number of documented drug interactions associated with CYP inhibition. In addition, drug interactions can also occur as a result of the induction of several human CYPs following long term drug treatment.

The mechanisms of CYP inhibition can be divided into 3 categories: (a) reversible inhibition; (b) quasi-irreversible inhibition; and (c) irreversible inhibition. In mechanistic terms, reversible interactions arise as a result of competition at the CYP active site and probably involve only the first step of the CYP catalytic cycle. On the other hand, drugs that act during and subsequent to the oxygen transfer step are generally irreversible or quasi-irreversible inhibitors. Irreversible and quasi-irreversible inhibition require at least one cycle of the CYP catalytic process.

Because human liver samples and recombinant human CYPs are now readily available, in vitro systems have been used as screening tools to predict the potential for in vivo drug interaction. Although it is easy to determine in vitro metabolic drug interactions, the proper interpretation and extrapolation of in vitro interaction data to in vivo situations require a good understanding of pharmacokinetic principles.

From the viewpoint of drug therapy, to avoid potential drug-drug interactions, it is desirable to develop a new drug candidate that is not a potent CYP inhibitor or inducer and the metabolism of which is not readily inhibited by other drugs. In reality, drug interaction by mutual inhibition between drugs is almost inevitable, because CYP-mediated metabolism represents a major route of elimination of many drugs, which can compete for the same CYP enzyme.

The clinical significance of a metabolic drug interaction depends on the magnitude of the change in the concentration of active species (parent drug and/or active metabolites) at the site of pharmacological action and the therapeutic index of the drug. The smaller the difference between toxic and effective concentration, the greater the likelihood that a drug interaction will have serious clinical consequences. Thus, careful evaluation of potential drug interactions of a new drug candidate during the early stage of drug development is essential.


Adis International Limited Indinavir Terfenadine Human Liver Microsome Stiripentol 
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  1. 1.
    Guengerich FP. Enzymatic oxidation of xenobiotic chemicals. Crit Rev Biochem Mol Biol 1990; 25: 97–103.PubMedCrossRefGoogle Scholar
  2. 2.
    Gonzalez FJ. Human cytochromes P450: problems and prospects. Trends Pharmacol Sci 1992; 13: 346–52.PubMedCrossRefGoogle Scholar
  3. 3.
    Guengerich FP. Human cytochrome P450 enzymes. In: Ortiz de Montellano PR, editor. Cytochrome P450: structure, mechanism, and biochemistry [chapter 14]. 2nd ed. New York: Plenum Press, 1995: 473–535.Google Scholar
  4. 4.
    Parkinson A. An overview of current cytochrome P450 technology for assessing the safety and efficacy of new materials. Toxicol Pathol 1996; 24: 45–57.CrossRefGoogle Scholar
  5. 5.
    Shen WW. Cytochrome P450 monooxygenases and interactions of psychotropic drugs: a five-year update. Int J Psychiatry Med 1995; 25: 277–90.PubMedCrossRefGoogle Scholar
  6. 6.
    Riesenman C. Antidepressant drug interactions and the cytochrome P450 system: a critical appraisal. Pharmacotherapy 1995; 15: 84S–99S.PubMedGoogle Scholar
  7. 7.
    Somogyi A, Muirhead M. Pharmacokinetic interactions of cimetidine 1987. Clin Pharmacokinet 1987; 12: 321–66.PubMedCrossRefGoogle Scholar
  8. 8.
    Nelson DR, Koymans L, Kamataki T, et al. P450 superfamily, update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1996; 6: 1–42.PubMedCrossRefGoogle Scholar
  9. 9.
    Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P450 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 1994; 270: 414–23.PubMedGoogle Scholar
  10. 10.
    Guengerich FP, Turvy CG. Comparison of levels of human microsomal cytochrome P450 enzymes and epoxide hydrolase in normal and disease states using immunochemical analysis of surgical samples. J Pharmacol Exp Ther 1991; 256: 1189–94.PubMedGoogle Scholar
  11. 11.
    Ged C, Umbenhauer DR, Beilew TM, et al. Characterization of cDNAs, mRNAs and proteins related to human liver microsomal cytochrome P450 (S)-mephenytoin 4′-hydroxylase. Biochemistry 1988; 27: 6929–40.PubMedCrossRefGoogle Scholar
  12. 12.
    Romkes M, Faletto MB, Blaisdell JA, et al. Cloning and expression of complementary DNAs for multiple numbers of the human cytochrome P450 II C subfamily. Biochemistry 1991; 30: 3247–55.PubMedCrossRefGoogle Scholar
  13. 13.
    Meyer UA, Skoda RC, Zanger UM, et al. The genetic polymorphism of debrisoquine/sparteine metabolism: molecular mechanisms. In: Kalow W, editor. Pharmacogenetics of drug metabolism. New York: Pergamon Press, 1992: 609–23.Google Scholar
  14. 14.
    Wilkinson GR, Guengerich FP, Branch RA. Genetic polymorphism of S-mephenytoin hydroxylation. In: Kalow W, editor. Pharmacogenetics of drug metabolism. New York: Pergamon Press, 1992: 657–85.Google Scholar
  15. 15.
    Meyer UA. The molecular basis of genetic polymorphisms of drug metabolism. J Pharm Pharmacol 1994; 46 Suppl. 1: 409–15.PubMedGoogle Scholar
  16. 16.
    Alvan G, Bechtel P, Iselius L, et al. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 1990; 39: 533–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Bertilsson L, Lou YQ, Du YL, et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther 1992; 51: 388–97.PubMedCrossRefGoogle Scholar
  18. 18.
    Johansson I, Lundqvist E, Bertilsson L, et al. Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci USA 1993; 90: 11825–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Dahl M-L, Johansson I, Bertilsson L, et al. Ultrarapid hydroxylation of debrisoquine in a Swedish population: analysis of the molecular genetic basis. J Pharmacol Exp Ther 1995; 274: 516–20.PubMedGoogle Scholar
  20. 20.
    Aklillu E, Persson I, Bertilsson L, et al. Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1995; 278: 441–6.Google Scholar
  21. 21.
    Kalow W, Bertilsson L. Interethnic factors affecting drug response. In: Testa B, Meyer UA, editors. Advantages in drug research. New York: Academic Press, 1994: 1–53.Google Scholar
  22. 22.
    Horai Y, Nakano M, Ishizaki T, et al. Metoprolol and mephenytoin oxidation in far eastern oriental subjects. Japanese versus mainland Chinese. Clin Pharmacol Ther 1989; 46: 198–207.Google Scholar
  23. 23.
    Guengerich FP. Catalytic selectivity of human cytochrome P450 enzymes: relevance to drug metabolism and toxicity. Toxicol Lett 1994; 70: 133–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Guengerich FP, Shimada T. Human cytochrome P450 enzymes and chemical carcinogenesis. In: Jeffery EH, editor. Human drug metabolism: from molecular biology to man. Boca Raton (FL): CRC Press, 1992: 5–12.Google Scholar
  25. 25.
    Estabrook RW. Cytochrome P450: from a single protein to a family of proteins — with some personal reflections. In: Ioannides CI, editor. Cytochromes P450: metabolic and toxicologixal aspects. Boca Raton: CRC Press, 1996: 3–28.Google Scholar
  26. 26.
    Correia MA, Oritz de Montellano PR. Inhibitors of cytochrome P450 and possibilities for their therapeutic application. In: Ruckpauland K, Rein H, editors. Medicinal implications in cytochrome P450 catalyzed biotransformations [chapter 3]. Berlin: Akademie Verlag, 1993: 74–146.Google Scholar
  27. 27.
    Ortiz de Montellano PR, Correia MA. Inhibition of cytochrome P450 enzymes. In: Ortiz de Montellano PR, editor. Cytochrome P450: structure, mechanism and biochemistry. New York: Plenum Press, 1995: 305–64.Google Scholar
  28. 28.
    Halpert JR. Structural basis of selective cytochrome P450 inhibition. Ann Pharmacol Toxicol 1995; 35: 29–53.CrossRefGoogle Scholar
  29. 29.
    Wilkinson CF, Hetnarski K, Cantwell GP, et al. Structure-activity relationships in the effects of 1-alkylimidazoles on microsomal oxidation in vitro and in vivo. Biochem Pharmacol 1974; 23: 2377–86.PubMedCrossRefGoogle Scholar
  30. 30.
    Rogerson TD, Wilkinson CF, Hetnarski K. Steric factors in the inhibitory interactions of imidazoles with microsomal enzymes. Biochem Pharmacol 1977; 26: 1039–42.PubMedCrossRefGoogle Scholar
  31. 31.
    Pelkonen O, Puurunen J. The effect of cimetidine on in vitro and in vivo microsomal drug metabolism in the rat. Biochem Pharmacol 1980; 29: 3075–80.PubMedCrossRefGoogle Scholar
  32. 32.
    Gascon MP, Oestreicher-Kondo M, Dayer P. Comparative effects of imidazole antifungals on liver monooxygenases [abstract]. Clin Pharmacol Ther 1991; 49: 158.Google Scholar
  33. 33.
    Richardson K. The discovery of fluconazole. Drug News Perspect 1993; 6: 299–303.Google Scholar
  34. 34.
    Jonen HG, Hüthwohl B, Kahl R, et al. Influence of pyridine and some pyridine derivatives on spectral properties of reduced microsomes and on microsomal drug metabolizing activity. Biochem Pharmacol 1974; 23: 1319–29.PubMedCrossRefGoogle Scholar
  35. 35.
    Dominguez OV, Samuels LT. Mechanism of inhibition of adrenal steroid 11-beta-hydroxylase by metyrapone (metopirone). Endocrinology 1963; 73: 304–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Temple TE, Liddle GW. Inhibitors of adrenal steroid biosynthesis. Annu Rev Pharmacol 1970; 10: 199–218.PubMedCrossRefGoogle Scholar
  37. 37.
    Winchell GA, McCrea JB, Tomasko L, et al. Study of potential pharmacokinetic interaction between indinavir and clarithromycin. Pharm Res 1996; 13 Suppl.: S434.Google Scholar
  38. 38.
    Lesca P, Rafidinarivo P, Lecointe P, et al. A class of strong inhibitors of microsomal monooxygenases: the ellipticines. Chem Biol Interact 1979; 24: 189–98.PubMedCrossRefGoogle Scholar
  39. 39.
    Boobis AR, Sesardic D, Murray BP, et al. Species variation in the response of cytochrome P450-dependentmonooxygenase system to inducers and inhibitors. Xenobiotics 1990; 20: 1139–61.CrossRefGoogle Scholar
  40. 40.
    Murray M. In vitro effects of quinoline derivatives on cytochrome P450 and aminopyrine N-demethylase activity in rat hepatic microsomes. Biochem Pharmacol 1984; 33: 3277–81.PubMedCrossRefGoogle Scholar
  41. 41.
    Murray M, Farrell GC. Mechanistic aspects of the inhibition of microsomal drug oxidation by primaquine. Biochem Pharmacol 1986; 35: 2149–55.PubMedCrossRefGoogle Scholar
  42. 42.
    Riviere JH, Back DJ. Effect of mefloquine on hepatic drug metabolism in the rat: comparative study with primaquine. Biochem Pharmacol 1985; 34: 567–71.PubMedCrossRefGoogle Scholar
  43. 43.
    Elcombe CR, Bridges JW, Gray TJB, et al. Studies on the interaction of safrole with rat hepatic microsomes. Biochem Pharmacol 1975; 24: 1427–33.CrossRefGoogle Scholar
  44. 44.
    Dickins M, Elcombe CR, Moloney SJ, et al. Further studies on the dissociation of the isosafrole metabolite-cytochrome P450 complex. Biochem Pharmacol 1979; 28: 231–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Ullrich V, Schnabel KH. Formation and binding of carbanions by cytochrome P450 of liver microsomes. Drug Metab Dispos 1973; 1: 176–83.PubMedGoogle Scholar
  46. 46.
    Murray M, Hetnarski K, Wilkinson CF. Selective inhibitory interactions of alkoxymethylenedioxybenzenes towards monooxygenase activity in rat hepatic microsomes. Xenobiotics 1985; 15: 369–7.CrossRefGoogle Scholar
  47. 47.
    Franklin MR. Inhibition of mixed-function oxidations by substrates forming reduced cytochrome P450 metabolicintermediate-complexes. Pharmacol Ther 1977; 2: 227–45.Google Scholar
  48. 48.
    Elcombe CR, Bridges JW, Nimmo-Smith RH, et al. Cumene hydroperoxide-mediated formation of inhibited complexes of methylenedioxyphenyl compounds with cytochrome P450. Biochem Soc Trans 1975; 3: 967–70.Google Scholar
  49. 49.
    Yu LS, Wilkinson CF, Anders MW. Generation of carbon monoxide during the microsomal metabolism of methylenedioxyphenyl compounds. Biochem Pharmacol 1980; 29: 1113–22.PubMedCrossRefGoogle Scholar
  50. 50.
    Hodgson E, Philpot RM. Interaction of methylenedioxyphenyl (1,3-benzodixole) compounds with enzymes and their effects on mammals. Drug Metab Rev 1974; 3: 231–301.PubMedCrossRefGoogle Scholar
  51. 51.
    Pessayre D, Descatoire V, Tinel M, et al. Self-induction by oleandomycin of its own transformation into a metabolite forming an inactive complex with reduced cytochrome P450: comparison with troleandomycin. J Pharmacol Exp Ther 1982; 221: 215–21.PubMedGoogle Scholar
  52. 52.
    Delaforge M, Jaouen M, Mansuy D. Dual effects of macrolide antibiotics on rat liver cytochrome P450 induction and formation of metabolic complexes: a structure activity relationship. Biochem Pharmacol 1983; 32: 2309–18.PubMedCrossRefGoogle Scholar
  53. 53.
    Watkins PB, Wrighton SA, Schuetz EG, et al. Macrolide antibiotics inhibit the degradation of the glucocorticoid-responsive cytochrome P450P in rat hepatocytes in vivo and in primary monolayer culture. J Biol Chem 1986; 261: 6264–71.PubMedGoogle Scholar
  54. 54.
    Pessayre D, Larrey D, Vitaux J, et al. Formation of an inactive cytochrome P450 Fe (II)-metabolite complex after administration of troleandomycin in humans. Biochem Pharmacol 1982; 31: 1699–704.PubMedCrossRefGoogle Scholar
  55. 55.
    Danan G, Descatoire V, Pessayre D. Self-induction by erythromycin of its own transformation into a metabolite forming an inactive complex with reduced cytochrome P450. J Pharmacol Exp Ther 1981; 218: 509–14.PubMedGoogle Scholar
  56. 56.
    Larrey D, Funck-Brentano C, Breil P, et al. Effects of erythromycin on hepatic drug metabolizing enzymes in humans. Biochem Pharmacol 1983; 32: 1063–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Reidy GF, Mahta I, Murray M. Inhibition of oxidative drug metabolism by orphenadrine: in vitro and in vivo evidence for isozyme-specific complexation of cytochrome P450 and inhibition kinetics. Mol Pharmacol 1989; 35: 736–43.PubMedGoogle Scholar
  58. 58.
    Buening MK, Franklin MR. SKF-525A inhibition, induction and 452-nm complex formation. Drug Metab Dispos 1976; 4: 244–55.PubMedGoogle Scholar
  59. 59.
    Murray M. Isozyme-selective complexation of cytochrome P450 in hepatic microsomes from SKF-525A-induced rats. Arch Biochem Biophys 1988; 262: 381–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Mahy JP, Battioni P, Mansuy D, et al. Iron porphyrin-nitrene complexes: preparation from 1,1-dialkylhydrazines: electronic structure from NMR, Mössbauer, and the magnetic susceptibility studies and crystal structure of the [tetrakis(p-chlorophenyl)porphyrinato-(2,2, 6,6,-tetramethyl-l-piperidyl)nitrene] iron complex. J Am Chem Soc 1984; 106: 1699–706.CrossRefGoogle Scholar
  61. 61.
    Muakkasah SF, Bidlack WR, Yang WCT. Mechanism of the inhibitory action of isoniazid on microsomal drug metabolism. Biochem Pharmacol 1981; 30: 1651–8.CrossRefGoogle Scholar
  62. 62.
    Kutt H, Brennan R, Dehajia H, et al. Diphenylhydantoin intoxication: a complication of isoniazid therapy. Am Rev Respir Dis 1970; 101: 377–84.PubMedGoogle Scholar
  63. 63.
    Rosenthal AR, Self TH, Baker ED, et al. Interaction of isoniazid and warfarin. JAMA 1977; 238: 2177.PubMedCrossRefGoogle Scholar
  64. 64.
    Silverman RB. Criteria for mechanism-based enzyme inactivation. In: Mechanism-based enzyme inactivation: chemistry and enzymology [chapter 1]. Boca Raton (FL): CRC Press, 1988: 3–27.Google Scholar
  65. 65.
    Ortiz de Montellano PR. Suicide substrate for drug metabolizing enzymes: mechanisms and biological consequences. In: Gibson GG, editor. Progress in drug metabolism. Vol. 11. New York: Taylor & Francis, 1988: 99–148.Google Scholar
  66. 66.
    Bornheim LM, Underwood MC, Caldera P, et al. Inactivation of multiple hepatic cytochrome P450 isozymes in rats by allyliso-propylacetamide: mechanistic implications. Mol Pharmacol 1987; 32: 299–308.PubMedGoogle Scholar
  67. 67.
    Bornheim LM, Kotaka AN, Correia MA. Differential haeminmediated restoration of cytochrome P450 N-demethylases after inactivation by allisopropylacetamide. Biochem J 1985; 227: 277–86.PubMedGoogle Scholar
  68. 68.
    Guengerich FP. Oxidation of 17(X-ethynylestradiol by human liver cytochrome P450. Mol Pharmacol 1988; 33: 500–8.PubMedGoogle Scholar
  69. 69.
    De Matteis F, Hollands C, Gibbs AH, et al. Inactivation of cytochrome P450 and production of N-alkylated porphyrins caused in hepatocytes by substituted dihydropyridines: structural requirements for loss haem and alkylation of the pyrrole nitrogen atom. FEBS Lett 1982; 145: 87–92.PubMedCrossRefGoogle Scholar
  70. 70.
    Halpert JR. Covalent modification of lysine during the suicide inactivation of rat liver cytochrome P450 by chloramphenicol. Biochem Pharmacol 1981; 30: 875–81.PubMedCrossRefGoogle Scholar
  71. 71.
    Halpert JR, Miller NE, Gorsky LD. On the mechanism of the inactivation of the major phenobarbital-inducible isozymes of rat liver cytochrome P450 by chloramphenicol. J Biol Chem 1985; 260: 8397–403.PubMedGoogle Scholar
  72. 72.
    Halpert JR, Balfour C, Miller NE, et al. Isozyme selectivity of the inhibition of rat liver cytochromes P450 by chloramphenicol in vivo. Mol Pharmacol 1985; 28: 290–6.PubMedGoogle Scholar
  73. 73.
    Roberts ES, Hopkins NE, Alworth WL, et al. Mechanism-based inactivation of cytochrome P450 2B1 by 2-ethynylnaphthalene: identification of an active-site peptide. Chem Res Toxicol 1993; 6: 470–9.PubMedCrossRefGoogle Scholar
  74. 74.
    Lopez-Garcia MP, Dansette PM, Mansuy D. Thiophene derivatives as new mechanism-based inhibitors of cytochromes P450: inactivation of yeast-expressed human liver P450 2C9 by tienilic acid. Biochemistry 1993; 33: 166–75.CrossRefGoogle Scholar
  75. 75.
    Jin L, Baillie TA. Metabolism of chemoprotective agent diallyl sulfide to glutathione conjugates in rats. Chem Res Toxicol 1997; 10: 318–27.PubMedCrossRefGoogle Scholar
  76. 76.
    Bondon A, McDonald T, Harris TM, et al. Oxidation of cycloalkylamine by cytochrome P450. J Biol Chem 1989; 264: 1985–97.Google Scholar
  77. 77.
    Decker CJ, Rashed MS, Baillie TA, et al. Oxidative metabolism of spironolactone: evidence for involvement of electrophilic thiosteroid species in drug-mediated destruction of rat hepatic cytochrome P450. Biochemistry 1989; 28: 5128–36.PubMedCrossRefGoogle Scholar
  78. 78.
    Conney AH, Miller EC, Miller JA. The metabolism of methylated aminoazo dyes: V. Evidence for induction of enzyme systems in the rat by 3-methyl-cholanthrene. Cancer Res 1956; 16: 450–9.Google Scholar
  79. 79.
    Remmer H. Die Beschleunigung des Evipanabbaues unter der Wirkung von Barbituraten. Naturwissenschaften 1958; 8: 189–91.CrossRefGoogle Scholar
  80. 80.
    Whitlock JP, Denison MS. Induction of cytochrome P450 enzymes that metabolize xenobiotics. In: Ortiz de Montellano PR, editor. Cytochrome P450: structure, mechanism and biochemistry [chapter 10]. 2nd ed. New York: Plenum Press, 1995: 367–90.Google Scholar
  81. 81.
    Okey AB. Enzyme induction in the cytochrome P450 system. In: Kalow W, editor. Pharmacogenetics of drug metabolism [chapter 19]. New York: Pergamon Press, 1992; 549–608.Google Scholar
  82. 82.
    Koop DR, Crump BC, Nordblom GD, et al. Immunochemical evidence for induction of alcohol-oxidizing cytochrome P450 of rabbit liver microsomes by diverse agents: ethanol, imidazole, trichloroethylene, acetone, pyrazole and isoniazid. Proc Natl Acad Sci U S A 1985; U S A 82: 4065–9.PubMedCrossRefGoogle Scholar
  83. 83.
    Song BJ, Veech RL, Park SS, et al. Induction of rat hepatic N-nitrosodimethylamine demethylase by acetone is due to protein stabilization. J Biol Chem 1989; 264: 3568–72.PubMedGoogle Scholar
  84. 84.
    Song BJ, Matsunaga T, Hardwick JP, et al. Stabilization of cytochrome P450J messenger ribonucleic acid in the diabetic rat. Mol Endocrinol 1987; 1: 542–7.PubMedCrossRefGoogle Scholar
  85. 85.
    Dong Z, Hong J, Ma Q, et al. Mechanism of induction of cytochrome P450ac (P450j) in chemically induced and spontaneously diabetic rats. Arch Biochem Biophs 1988; 263: 29–35.CrossRefGoogle Scholar
  86. 86.
    Wattenberg LW, Leong JL. Inhibition of the carcinogenic action of 7,12-dimethylbenz(a)anthracene by β-naphthoflavone. Proc Soc Exp Biol Med 1968; 128: 940–3.Google Scholar
  87. 87.
    DiGiovanna J, Berry DL, Juchau MR, et al. 2,3,7,8-Tetrachlorodibenzo-p-dioxin: potent anticarcinogenic activity in CD-I mice. Biochem Biophys Res Commun 1979; 86: 577–84.CrossRefGoogle Scholar
  88. 88.
    Gelboin HV. Benzo(a)pyrene metabolism, activation and carcinogenesis: role of mixed function oxidases and related enzymes. Pharmacol Rev 1980; 60: 1107–66.Google Scholar
  89. 89.
    Ioannides C, Parke DV. Induction of cytochrome P4501 as an indicator of potential chemical carcinogenesis. Drug Metab Rev 1993; 25: 485–501.PubMedCrossRefGoogle Scholar
  90. 90.
    Beresford AP. CYP1A1: friend or foe? Drug Metab Rev 1993; 25: 503–17.PubMedCrossRefGoogle Scholar
  91. 91.
    Bock KW, Lipp H-P, Bock-Hennig BS. Induction of drug-metabolizing enzymes by xenobiotics. Xenobiotica 1990; 20: 1101–11.PubMedCrossRefGoogle Scholar
  92. 92.
    McDonnell WM, Scheiman JM, Traber PG. Induction of cytochrome P450 IA genes (CYP1A) by omeprazole in the human alimentary tract. Gastroenterology 1993; 103: 1500–16.Google Scholar
  93. 93.
    Diaz D, Fabre I, Daujat M, et al. Omeprazole is an aryl hydrocarbon-like inducer of human hepatic cytochrome P450. Gastroenterology 1990; 99: 737–47.PubMedGoogle Scholar
  94. 94.
    Rice JM, Diwan BA, Ward JM, et al. Phenobarbital and related compounds: approaches to interspecies extrapolation. Prog Clin Biol Res 1992; 374: 231–49.PubMedGoogle Scholar
  95. 95.
    Strolin Benedetti M, Dostert P. Induction and autoinduction properties of rifamycin derivatives: a review of animal and human studies. Environ Health Perspect 1994; 102 Suppl. 9: 101–5.PubMedCrossRefGoogle Scholar
  96. 96.
    Nebert DW, Gonzalez FJ. The P450 gene superfamily. In: Ruckpaul K, Rein H, editors. Principles, mechanisms and biological consequences of induction. London: Taylor & Francis, 1990: 35–61.Google Scholar
  97. 97.
    Peck CC, Temple R, Collins JM. Understanding consequences of concurrent therapies. JAMA 1993; 269: 1550–2.PubMedCrossRefGoogle Scholar
  98. 98.
    Wrington S, Ring BJ. Inhibition of human CYP3A catalyzed l’-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine and nizatidine. Pharm Res 1994; 11: 921–4.CrossRefGoogle Scholar
  99. 99.
    Segel RH. Simple inhibition systems. In: Segel IH, editor. Enzyme kinetics [chapter 3]. Wiley-Interscience. New York: John Wiley & Sons, 1975: 100–60.Google Scholar
  100. 100.
    Levy RH, Dumain MS, Cook JL. Time-dependent kinetics: V. Time course of drug levels during enzyme induction (onecompartment model). J Pharmacokinet Biopharm 1979; 7: 557–78.Google Scholar
  101. 101.
    Levy RH, Dumain MS. Time-dependent kinetics: VI. Direct relationship between equations from drug levels during induction and those involving constant clearance. J Pharm Sci 1979; 68: 934–6.Google Scholar
  102. 102.
    Levy RH, Lai AA, Dumain MS. Time-dependent kinetics: IV. Pharmacokinetic theory of enzyme induction. J Pharm Sci 1979; 68: 398–9.Google Scholar
  103. 103.
    Chiba M, Hensleigh M, Nishime JA, et al. Role of cytochrome P450 3A4 in human metabolism of MK-639, a potent human immunodeficiency virus protease inhibitor. Drug Metab Dispos 1996; 24: 307–14.PubMedGoogle Scholar
  104. 104.
    Cashman JR, Young Z, Yang L, et al. Stereo- and regio-selective N- and S-oxidation of tertiary amines and Sulfides in the presence of adult human liver microsomes. Drug Metab Dispos 1993; 21: 492–501.PubMedGoogle Scholar
  105. 105.
    Inaba T, Tait A, Nakano M, et al. Metabolism of diazepam in vitro by human liver microsomes: independent variability of N-demethylation and C3-hydroxylation. Drug Metab Dispos 1988; 16: 605–8.PubMedGoogle Scholar
  106. 106.
    Yasumori T, Nagata K, Yang SK, et al. Cytochrome P450 mediated metabolism of diazepam in human and rat: involvement of human CYP 2C in N-demethylation in the substrate concentration-dependent manner. Pharmacogenetics 1993; 3: 291–301.PubMedCrossRefGoogle Scholar
  107. 107.
    Lampen A, Christians U, Guengerich FP, et al. Metabolism of the immunosuppressant tacrolimus in the small intestine: cytochrome P450, drug interactions, and interindividual variability. Drug Metab Dispos 1995; 23: 1315–24.PubMedGoogle Scholar
  108. 108.
    Bourrié M, Meunier V, Berger Y, et al. Cytochrome P450 isoform inhibitors as a tool for the investigation of metabolic reactions catalyzed by human liver microsomes. J Pharmacol Exp Ther 1996; 277: 321–32.PubMedGoogle Scholar
  109. 109.
    Von Moltke LL, Greenblatt DJ, Duan SX, et al. Inhibition of terfenadine metabolism in vitro by azole antifungal agents and by selective serotonin reuptake inhibitor antidepressants: relation to pharmacokinetic interactions in vivo. J Clin Psychopharmacol 1996; 16: 104–12.CrossRefGoogle Scholar
  110. 110.
    Kumar GN, Rodrigues AD, Buko AM, et al. Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) inhuman liver microsomes. J Pharmacol Exp Ther 1996; 277: 423–31.PubMedGoogle Scholar
  111. 111.
    Worboys PD, Bradbury A, Houston B. Kinetics of drug metabolism in rat liver slices: II. Comparison of clearance by liver slices and freshly isolated hepatocytes. Drug Metab Dispos 1996; 24: 676–81.Google Scholar
  112. 112.
    Ludden LK, Ludden TM, Collins JM, et al. Effect of albumin on the estimation, in vitro, of phenytoin Vmax and Km values: implications for clinical correction. J Pharmacol Exp Ther 1997; 282: 391–6.PubMedGoogle Scholar
  113. 113.
    Vickers AEM, Fischer V, Connors S, et al. Cyclosporin A metabolism in human liver, kidney, and intestine slices: comparison to rat and dog slices and human cell lines. Drug Metab Dispos 1992; 20: 802–9.PubMedGoogle Scholar
  114. 114.
    Vickers AEM, Connors S, Zollinger M, et al. The biotransformation of the ergot derivative CQA 206–291 in human, dog and rat liver slice cultures and prediction of in vivo plasma clearance. Drug Metab Dispos 1993; 21: 454–9.PubMedGoogle Scholar
  115. 115.
    Dogterom P. Development of a simple incubation system for metabolism studies with precision-cut liver slices. Drug Metab Dispos 1993; 21: 699–704.PubMedGoogle Scholar
  116. 116.
    Li AP. Primary hepatocyte culture as in vitro toxicological system. In: Gad S, editor. In vitro toxicology. New York: Raven Press, 1994: 195–220.Google Scholar
  117. 117.
    Li AP, Rasmussen A, Xu L, et al. Rifampicin induction of lidocaine metabolism in cultured human hepatocytes. J Pharmacol Exp Ther 1995; 274: 673–7.PubMedGoogle Scholar
  118. 118.
    Sidhu JS, Farin FM, Omiecinski CJ. Influence of extracellular matrix overlay on phenobarbital-mediated induction of CYP2B1, 2B2 and 3 Al genes in primary adult rat hepatocyte culture. Arch Biochem Biophys 1993; 301: 103–13.PubMedCrossRefGoogle Scholar
  119. 119.
    Wilkinson GR. Clearance approaches in pharmacology. Pharmacol Rev 1987; 39: 1–47.PubMedGoogle Scholar
  120. 120.
    Wilkinson GR, Shand DG. Aphysiological approach to hepatic drug clearance. Clin Pharmacol Ther 1975; 18: 377–90.PubMedGoogle Scholar
  121. 121.
    Lin JH. HIV protease inhibitors: from drug design to clinical studies. Adv Drug Deliv Rev 1997; 27: 215–33.PubMedCrossRefGoogle Scholar
  122. 122.
    Lin JH, Chiba M, Balani SK, et al. Species differences in the pharmacokinetics and metabolism of indinavir, a potent human immunodeficiency virus protease inhibitor. Drug Metab Dispos 1996; 24: 1111–20.PubMedGoogle Scholar
  123. 123.
    Lin JH. In vitro and in vivo drug interaction with indinavir. Symposium on Recent Advances in Drug-Drug Interaction; 1996 Dec 10–11; Washington, DC.Google Scholar
  124. 124.
    McCrea J, Woolf E, Sterret A, et al. Effects of ketoconazole and other P450 inhibitors on the pharmacokinetics of indinavir. Pharm Res 1996; 13 Suppl.: S485.Google Scholar
  125. 125.
    Lin JH, Sugiyama Y, Hanano M, et al. Effect of product inhibition on elimination kinetics of ethoxybenzamide in rabbits. Drug Metab Dispos 1984; 12: 253–6.PubMedGoogle Scholar
  126. 126.
    Lin JH, Hayashi M, Awazu S, et al. Correlation between in vitro and in vivo drug metabolism rate: oxidation of ethoxybenzamide in rat. J Pharmacokinet Biopharm 1978; 6: 327–37.PubMedGoogle Scholar
  127. 127.
    Lin JH, Sugiyama Y, Awazu S, et al. Physiological pharmacokinetics of ethoxybenzamide based on biochemical data obtained in vitro as well as on physiological data. J Pharmacokinet Biopharm 1982; 10: 649–61.PubMedGoogle Scholar
  128. 128.
    Ashforth EIL, Carlile DJ, Chenery R, et al. Prediction of in vivo disposition from in vitro systems: clearance of phenytoin and tolbutamide using rat hepatic microsomal and hepatocyte data. J Pharmacol Exp Ther 1995; 274: 761–6.PubMedGoogle Scholar
  129. 129.
    Houston JB. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol 1994; 47: 1469–74.PubMedCrossRefGoogle Scholar
  130. 130.
    Von Moltke LL, Greenblatt DJ, Duan SX, et al. In vitro prediction of the terfenadine ketoconazole pharmacokinetic interaction. J Clin Pharmacol 1994; 34: 1222–7.Google Scholar
  131. 131.
    Tran A, Rey E, Pons G, et al. Influence of stiripentol on cytochrome P450-mediated metabolic pathways in humans: in vitro and in vivo comparison and calculation of in vivo inhibition constants. Clin Pharmacol Ther 1997; 62: 490–504.PubMedCrossRefGoogle Scholar
  132. 132.
    Von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, et al. Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake-inhibitor antidepressants, and by quinidine and ketoconazole: a model system to predict drug interactions in vivo. J Pharmacol Exp Ther 1994; 268: 1278–83.Google Scholar
  133. 133.
    Von Moltke LL, Greenblatt DJ, Schmider J, et al. In vitro approaches to predicting drug interactions in vivo. Biochem Pharmacol 1998; 55: 113–22.CrossRefGoogle Scholar
  134. 134.
    Bertz RJ, Granneman GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 1997; 32: 210–58.PubMedCrossRefGoogle Scholar
  135. 135.
    Lin JH. Pharmacokinetic and pharmacodynamic properties of histamine H2-receptor antagonists: relationship between intrinsic potency and effective plasma concentrations. Clin Pharmacokinet 1991; 20: 218–36.PubMedCrossRefGoogle Scholar
  136. 136.
    Knodell RG, Browne DG, Gwozdz GP, et al. Differential inhibition of individual human liver cytochromes P450 by cimetidine. Gastroenterology 1991; 101: 1680–91.PubMedGoogle Scholar
  137. 137.
    Chang T, Levine M, Bellward GD. Selective inhibition of rat hepatic microsomal cytochrome P450: II. Effect of the in vitro administration. J Pharmacol Exp Ther 1991; 260: 1450–5.Google Scholar
  138. 138.
    Chang T, Levine M, Bandiera SM, et al. Selective inhibition of rat hepatic microsomal cytochrome P450: I. Effect of the in vivo administration of cimetidine. J Pharmacol Exp Ther 1991; 260: 1441–9.Google Scholar
  139. 139.
    Pichard L, Gillet G, Fabre I, et al. Identification of the rabbit and human cytochromes P450 IIIA as the major enzymes involved in the N-demethylation of diltiazem. Drug Metab Dispos 1990; 18: 711–9.PubMedGoogle Scholar
  140. 140.
    Wang RW, Kari PH, Lu AYH, et al. Biotransformation of lovastatin: IV Identification of cytochrome P450 3Aproteins as the major enzymes responsible for the oxidative metabolism of lovastatin in rat and human liver microsomes. Arch Biochem Biophys 1991; 290: 355–61.PubMedCrossRefGoogle Scholar
  141. 141.
    Agbim NE, Brater DC, Hall SD. Interaction of diltiazem with lovastatin and pravastatin [abstract]. Clin Pharmacol Ther 1997; 61: 201.Google Scholar
  142. 142.
    Bensoussan C, Delaforge M, Mansuy D. Particular ability of cytochromes P450 3 A to form inhibitory P450-iron-metabolite complexes upon metabolic oxidation of amino drugs. Biochem Pharmacol 1995; 49: 591–602.PubMedCrossRefGoogle Scholar
  143. 143.
    Varhe A, Olkkola KT, Neuvonen PJ. Diltiazem enhances the effects of triazolam by inhibiting its metabolism. Clin Pharmacol Ther 1996; 59: 369–75.PubMedCrossRefGoogle Scholar
  144. 144.
    Backman TJ, Olkkola KT, Neuvonen PJ. Dose of midazolam should be reduced during diltiazem and verapamil treatments. Br J Clin Pharmacol 1994; 37: 221–5.PubMedCrossRefGoogle Scholar
  145. 145.
    Rowland M, Matin SB. Kinetics of drug-drug interactions. J Pharmacokinet Biopharm 1973; 1: 553–67.Google Scholar
  146. 146.
    Honig PK, Wortham DC, Zamani K, et al. Terfenadine-ketoconazole interaction: pharmacokinetic and electrocardiographic consequences. JAMA 1993; 269: 1535–9.CrossRefGoogle Scholar
  147. 147.
    Yun C, Okerholm RA, Guengerich FP. Oxidation of the antihistamine drug terfenadine in human liver microsomes: role of cytochrome P450 3A(4) in N-dealkylation and C-hydroxylation. Drug Metab Dispos 1993; 21: 403–9.PubMedGoogle Scholar
  148. 148.
    Woosley RL, Chen Y, Freiman JP, et al. Mechanism of the cardiotoxic action of terfenadine. JAMA 1993; 269: 1532–6.PubMedCrossRefGoogle Scholar
  149. 149.
    Monahan BP, Ferguson CL, Killeary ES, et al. Torsade de pointes occurring in association with terfenadine use. JAMA 1990; 264: 2788–90.PubMedCrossRefGoogle Scholar
  150. 150.
    Crane JK, Shih, H-T. Syncope and cardiac arrhythmia due to an interaction between itraconazeole and terfenadine. Am J Med 1993; 95: 445–6.PubMedCrossRefGoogle Scholar
  151. 151.
    Honig PK, Woosley RL, Zamani K, et al. Changes in pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther 1992; 52: 231–8.PubMedCrossRefGoogle Scholar
  152. 152.
    Lewis RJ, Träger WF, Chan KK, et al. Warfarin: stereochemical aspects of its metabolism and the interaction with phenylbutazone. J Clin Invest 1974; 53: 1607–17.PubMedCrossRefGoogle Scholar
  153. 153.
    Kunze KL, Wienkers LC, Thummel KE, et al. Warfarinfluconazole: inhibition of the human cytochrome P450-de-pendent metabolism of warfarin by fluconazole — in vitro studies. Drug Metab Dispos 1996; 24: 414–21.PubMedGoogle Scholar
  154. 154.
    Toon S, Hopkins KJ, Garstang FM, et al. Enoxacin-warfarin interactions: pharmacokinetics and stereochemical aspects. Clin Pharmacol Ther 1987; 44: 32–41.Google Scholar
  155. 155.
    Somogyi A, Gugler R. Drug interactions with cimetidine. Clin Pharmacokinet 1982; 7: 23–41.PubMedCrossRefGoogle Scholar
  156. 156.
    Niopas I, Toon S, Rowland M. Further insight into the stereos elective interaction between warfarin and cimetidine in man. Br J Clin Pharmacol 1991; 32: 508–11.PubMedCrossRefGoogle Scholar
  157. 157.
    Hamer A, Peter T, Mandel WJ, et al. Potentiation of warfarin anticoagulation by amiodarone. Circulation 1982; 65: 1025–9.PubMedCrossRefGoogle Scholar
  158. 158.
    Heimark LD, Wienkers L, Kunze K, et al. The mechanism of the interaction between amiodarone and warfarin in humans. Clin Pharmacol Ther 1992; 51: 398–407.PubMedCrossRefGoogle Scholar
  159. 159.
    Chen ZR, Somogyi AA, Bochner F. Polymorphic O-demethylation of codeine. Lancet 1988; II: 914–5.CrossRefGoogle Scholar
  160. 160.
    Ward SA, Helsby NA, Kjelbo E, et al. The activation of biguanide antimalarial proguanil co-segregates with the mephenytoin oxidation polymorphism: a panel study. Br J Clin Pharmacol 1991; 31: 689–92.PubMedCrossRefGoogle Scholar
  161. 161.
    Andersson T, Cederberg C, Edvardsson G, et al. Effect of omeprazole treatment on diazepam plasma levels in slow versus normal rapid metabolizers of omeprazole. Clin Pharmacol Ther 1990; 47: 79–85.PubMedCrossRefGoogle Scholar
  162. 162.
    Turgeon J, Pavlou HN, Wong W, et al. Genetically determined steady-state interaction between encainide and quinidine in patients with arrhythmias. J Pharmacol Exp Ther 1990; 255: 642–9.PubMedGoogle Scholar
  163. 163.
    Caraco Y, Wilkinson GR, Wood AJJ. Differences between white subjects and Chinese subjects in the in vivo inhibition of cytochrome P450s 2C19, 2D6 and 3A by omeprazole. Clin Pharmacol Ther 1996; 60: 396–404.PubMedCrossRefGoogle Scholar
  164. 164.
    Caraco Y, Tateishi T, Wood AJJ. Interethnic difference in omeprazole’s inhibition of diazepam metabolism. Clin Pharmacol Ther 1995; 58: 62–72.PubMedCrossRefGoogle Scholar
  165. 165.
    Lin JH, Chiba M, Chen I-W, et al. Time- and dose-dependent pharmacokinetics of L-754,394, an HIV protease inhibitor, in rats, dogs and monkeys. J Pharmacol Exp Ther 1995; 274: 264–9.PubMedGoogle Scholar
  166. 166.
    Yee GC, McGuire TR. Pharmacokinetic drug interaction with cyclosporin: I. Clin Pharmacokinet 1990; 19: 312–32.Google Scholar
  167. 167.
    Keogh A, Spratt P, McCosker C, et al. Ketoconazole to reduce the need for cyclosporine after cardiac transplantation. N Engl JMed 1995; 333: 628–33.CrossRefGoogle Scholar
  168. 168.
    Jones TE. The use of other drugs to allow a lower dosage of cyclosporin to be used: therapeutic and pharmacoeconomic considerations. Clin Pharmacokinet 1997; 32: 357–67.PubMedCrossRefGoogle Scholar
  169. 169.
    Kempf DJ, Marsh KC, Kumar G, et al. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob Agents Chemother 1997; 41: 654–60.PubMedGoogle Scholar
  170. 170.
    Zhou HH, Anthony LB, Wood AJJ, et al. Induction of polymorphic 4′-hydroxylation of S-mephenytoin by rifampicin. Br J Clin Pharmacol 1990; 30: 471–5.PubMedCrossRefGoogle Scholar
  171. 171.
    Combalbert J, Fabre I, Fabre G, et al. Metabolism of cyclosporin A: IV. Purification and identification of the rifampicininducible human liver cytochrome P450 (cyclosporin A oxidase) as a product of P450 3 Agene subfamily. Drug Metab Dispos 1984; 17: 197–207.Google Scholar
  172. 172.
    O’Reilly RA. Interactions of sodium warfarin and rifampicin studies in man. Ann Intern Med 1974; 81: 337–40.PubMedGoogle Scholar
  173. 173.
    Heimark LD, Gibaldi M, Trager WF, et al. The mechanism of warfarin-rifampicin drug interaction in humans. Clin Pharmacol Ther 1987; 423: 385–94.Google Scholar
  174. 174.
    Back DJ, Breckenridge AM, Crawford FE, et al. The effect of rifampicin on norethisterone pharmacokinetics. Eur J Clin Pharmacol 1979; 15: 193–7.PubMedCrossRefGoogle Scholar
  175. 175.
    Bolt HM, Kappus H, Bolt M. Effect of rifampicin treatment on the metabolism of estradiol and 17α-ethinylestradiol by human liver microsomes. Eur J Clin Pharmacol 1975; 8: 301–7.PubMedCrossRefGoogle Scholar
  176. 176.
    Daniels NJ, Hunnisett AG, Morris PJ. Interaction between cyclosporin and rifampicin. Lancet 1984; II: 639.CrossRefGoogle Scholar
  177. 177.
    Modry DL, Stinson EB, Oyer PE. Acute rejection and massive cyclosporine requirements in heart transplant recipients treated with rifampicin. Transplantation 1985; 39: 313–4.PubMedCrossRefGoogle Scholar
  178. 178.
    Campana C, Regazzi MB, Buggia I, et al. Clinically significant drug interactions with cyclosporin: an update. Clin Pharmacokinet 1996; 30: 141–79.PubMedCrossRefGoogle Scholar
  179. 179.
    Riva R, Albani F, Contin M, et al. Pharmacokinetic interactions between antiepileptic drugs: clinical considerations. Clin Pharmacokinet 1996; 31: 470–93.PubMedCrossRefGoogle Scholar
  180. 180.
    Breckenridge AM, Orme MLE. Clinical implications of enzyme induction. Ann NY Acad Sci 1971; 179: 421–31.PubMedCrossRefGoogle Scholar
  181. 181.
    Shaw PN, Houston JB, Rowland M, et al. Antipyrine metabolite kinetics in healthy human volunteers during multiple dosing of phenytoin and carbamazepine. Br J Clin Pharmacol 1985; 20: 611–8.PubMedCrossRefGoogle Scholar
  182. 182.
    Zhou HH, Anthony LB, Wood JJ, et al. Induction of polymorphic 4′-hydroxylation of S-mephenytoin by rifampicin. Br J Clin Pharmacol 1990; 30: 471–5.PubMedCrossRefGoogle Scholar
  183. 183.
    Rost KL, Brösicke H, Brockmöller J, et al. Increase of P450 IA2 activity by omeprazole: evidence by the 13C-[N3-methyl]-caffeine breath test in poor and extensive metabolizers of S-mephenytoin. Clin Pharmacol Ther 1992; 52: 170–80.PubMedCrossRefGoogle Scholar
  184. 184.
    Rost KL, Brösicke H, Heinemeyer G, et al. Specific and dosedependent enzyme induction by omeprazole in human beings. Hepatology 1994; 20: 1204–12.PubMedCrossRefGoogle Scholar
  185. 185.
    Smith DA, Chandler MHH, Shedlofsky SI, et al. Age-dependent stereoselective increase in the oral clearance of hexobarbitone isomers caused by rifampicin. Br J Clin Pharmacol 1991; 32: 735–9.PubMedGoogle Scholar
  186. 186.
    Branch RA, Herman RJ. Enzyme induction and β-adrenergic receptor blocking drugs. Br J Clin Pharmacol 1984; 17: 775–845.CrossRefGoogle Scholar
  187. 187.
    Twum-Barima Y, Finnigan T, Habash AI, et al. Impaired enzyme induction by rifampicin in the elderly. Br J Clin Pharmacol 1984; 17: 595–6.PubMedCrossRefGoogle Scholar
  188. 188.
    Vestal RE, Wood AJJ, Branch RA, et al. The effects of age and cigarette smoking on propranolol disposition. Clin Pharmacol Ther 1979; 26: 8–15.PubMedGoogle Scholar
  189. 189.
    Salem SAM. Reduced induction of drug metabolism in the elderly. Age Ageing 1978; 7: 68–73.PubMedCrossRefGoogle Scholar
  190. 190.
    Collste P, Seideman P, Borg KO, et al. Influence of pentobarbital on effect and plasma levels of alprenolol and 4-hydroxyalprenolol. Clin Pharmacol Ther 1979; 25: 423–7.PubMedGoogle Scholar
  191. 191.
    Mutschler E, Derendort H. Drug interaction. In: Mutschier E, Derendort H, editors. Drug actions: basic principles and therapeutic aspects [chapter 6]. Boca Raton (FL): CRC Press, 1995: 80–4.Google Scholar
  192. 192.
    Slattery JT, Nelson SD, Thummel KE. The complex interaction between ethanol and acetaminophen. Clin Pharmacol Ther 1996; 60: 241–6.PubMedCrossRefGoogle Scholar

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© Adis International Limited 1998

Authors and Affiliations

  1. 1.WP42-2, Drug MetabolismMerck Research LaboratoriesWest PointUSA

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