Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity

  • Siamak Cyrus KhojastehEmail author
  • Saileta Prabhu
  • Jane R. Kenny
  • Jason S. Halladay
  • Anthony Y. H. Lu


The majority of marketed small-molecule drugs undergo metabolism by hepatic Cytochrome P450 (CYP) enzymes (Rendic 2002). Since these enzymes metabolize a structurally diverse number of drugs, metabolism-based drug–drug interactions (DDIs) can potentially occur when multiple drugs are coadministered to patients. Thus, a careful in vitro assessment of the contribution of various CYP isoforms to the total metabolism is important for predicting whether such DDIs might take place. One method of CYP phenotyping involves the use of potent and selective chemical inhibitors in human liver microsomal incubations in the presence of a test compound. The selectivity of such inhibitors plays a critical role in deciphering the involvement of specific CYP isoforms. Here, we review published data on the potency and selectivity of chemical inhibitors of the major human hepatic CYP isoforms. The most selective inhibitors available are furafylline (in co-incubation and pre-incubation conditions) for CYP1A2, 2-phenyl-2-(1-piperidinyl)propane (PPP) for CYP2B6, montelukast for CYP2C8, sulfaphenazole for CYP2C9, (–)-N-3-benzyl-phenobarbital for CYP2C19 and quinidine for CYP2D6. As for CYP2A6, tranylcypromine is the most widely used inhibitor, but on the basis of initial studies, either 3-(pyridin-3-yl)-1H-pyrazol-5-yl)methanamine (PPM) and 3-(2-methyl-1H-imidazol-1-yl)pyridine (MIP) can replace tranylcypromine as the most selective CYP2A6 inhibitor. For CYP3A4, ketoconazole is widely used in phenotyping studies, although azamulin is a far more selective CYP3A inhibitor. Most of the phenotyping studies do not include CYP2E1, mostly because of the limited number of new drug candidates that are metabolized by this enzyme. Among the inhibitors for this enzyme, 4-methylpyrazole appears to be selective.


Ticlopidine Montelukast Human Liver Microsome Tranylcypromine Sulfaphenazole 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would also like to acknowledge the editorial contribution of Ronitte Libedinsky and helpful comments by Peter Fan.


  1. Atkinson A, Kenny JR, Grime K (2005) Automated assessment of time-dependent inhibition of human cytochrome P450 enzymes using liquid chromatography–tandem mass spectrometry analysis. Drug Metab Dispos 33:1637–1647PubMedGoogle Scholar
  2. Baldwin SJ, Bloomer JC, Smith GJ, Ayrton AD, Clarke SE, Chenery RJ (1995) Ketoconazole and sulphaphenazole as the respective selective inhibitors of P4503A and 2C9. Xenobiotica 25:261–270PubMedGoogle Scholar
  3. Baldwin SJ, Clarke SE, Chenery RJ (1999) Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol 48:424–432PubMedGoogle Scholar
  4. Baune B, Furlan V, Taburet AM, Farinotti R (1999) Effect of selected antimalarial drugs and inhibitors of cytochrome P-450 3A4 on halofantrine metabolism by human liver microsomes. Drug Metab Dispos 27:565–568PubMedGoogle Scholar
  5. Becquemont L, Le Bot MA, Riche C, Funck-Brentano C, Jaillon P, Beaune P (1998) Use of heterologously expressed human cytochrome P450 1A2 to predict tacrine–fluvoxamine drug interaction in man. Pharmacogenetics 8:101–108PubMedGoogle Scholar
  6. Bell L, Bickford S, Nguyen PH, Wang J, He T, Zhang B, Friche Y, Zimmerlin A, Urban L, Bojanic D (2008) Evaluation of fluorescence- and mass spectrometry-based CYP inhibition assays for use in drug discovery. J Biomol Screen 13:343–353PubMedGoogle Scholar
  7. Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J, King SP, Miwa G, Ni L, Kumar G, McLeod J, Obach RS, Roberts S, Roe A, Shah A, Snikeris F, Sullivan JT, Tweedie D, Vega JM, Walsh J, Wrighton SA (2003) The conduct of in vitro and in vivo drug–drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab Dispos 31:815–832PubMedGoogle Scholar
  8. Bloomer JC, Baldwin SJ, Smith GJ, Ayrton AD, Clarke SE, Chenery RJ (1994) Characterisation of the cytochrome P450 enzymes involved in the in vitro metabolism of granisetron. Br J Clin Pharmacol 38:557–566PubMedGoogle Scholar
  9. Bourrié M, Meunier V, Berger Y, Fabre GJ (1996) Cytochrome P450 isoform inhibitors as a tool for the investigation of metabolic reactions catalyzed by human liver microsomes. Pharmacol Exp Ther 277:321–332Google Scholar
  10. Brøsen K, Skjelbo E, Rasmussen BB, Poulsen HE, Loft S (1993) Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 45:1211–1214PubMedGoogle Scholar
  11. Bun SS, Ciccolini J, Bun H, Aubert C, Catalin J (2003) Drug interactions of paclitaxel metabolism in human liver microsomes. J Chemother 15:266–274PubMedGoogle Scholar
  12. Burke MD, Thompson S, Weaver RJ, Wolf CR, Mayer RT (1994) Cytochrome P450 selectivities of alkoxyresorufin O-dealkylation in human and rat liver. Biochem Pharmacol 48:923–936PubMedGoogle Scholar
  13. Cai X, Wang RW, Edom RW, Evans DC, Shou M, Rodrigues AD, Liu W, Dean DC, Baillie TA (2004) Validation of (–)-N-3-benzyl-phenobarbital as a selective inhibitor of CYP2C19 in human liver microsomes. Drug Metab Dispos 32:584–586PubMedGoogle Scholar
  14. Chan WK, Delucchi AB (2000) Resveratrol, a red wine constituent, is a mechanism-based inactivator of cytochrome P450 3A4. Life Sci 67:3103–3112PubMedGoogle Scholar
  15. Chang TK, Weber GF, Crespi CL, Waxman DJ (1993) Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Cancer Res 53:5629–5637PubMedGoogle Scholar
  16. Chang TK, Gonzalez FJ, Waxman DJ (1994) Evaluation of triacetyloleandomycin, alpha-naphthoflavone and diethyldithiocarbamate as selective chemical probes for inhibition of human cytochromes P450. Arch Biochem Biophys 311:437–442PubMedGoogle Scholar
  17. Chang TK, Chen J, Yeung EY (2006) Effect of Ginkgo biloba extract on procarcinogen-bioactivating human CYP1 enzymes: identification of isorhamnetin, kaempferol, and quercetin as potent inhibitors of CYP1B1. Toxicol Appl Pharmacol 213:18–26PubMedGoogle Scholar
  18. Chaudhary A, Willett KL (2006) Inhibition of human cytochrome CYP 1 enzymes by flavonoids of St. John’s wort. Toxicology 217:194–205PubMedGoogle Scholar
  19. Chiba K, Kobayashi K, Manabe K, Tani M, Kamataki T, Ishizaki T (1993) Oxidative metabolism of omeprazole in human liver microsomes: cosegregation with S-mephenytoin 4′-hydroxylation. J Pharmacol Exp Ther 266:52–59PubMedGoogle Scholar
  20. Chiba M, Xu X, Nishime JA, Balani SK, Lin JH (1997) Hepatic microsomal metabolism of montelukast, a potent leukotriene D4 receptor antagonist, in humans. Drug Metab Dispos 25:1022–1031PubMedGoogle Scholar
  21. Ching MS, Blake CL, Ghabrial H, Ellis SW, Lennard MS, Tucker GT, Smallwood RA (1995) Potent inhibition of yeast-expressed CYP2D6 by dihydroquinidine, quinidine, and its metabolites. Biochem Pharmacol 50:833–837PubMedGoogle Scholar
  22. Chun J, Kent UM, Moss RM, Sayre LM, Hollenberg PF (2000) Mechanism-based inactivation of cytochromes P450 2B1 and P450 2B6 by 2-phenyl-2-(1-piperidinyl)propane. Drug Metab Dispos 28:905–911PubMedGoogle Scholar
  23. Clarke SE, Ayrton AD, Chenery RJ (1994) Characterization of the inhibition of P4501A2 by furafylline. Xenobiotica 24:517–526PubMedGoogle Scholar
  24. Cohen LH, Remley MJ, Raunig D, Vaz A (2003) In vitro drug interactions of cytochrome p450: an evaluation of fluorogenic to conventional substrates. Drug Metab Dispos 31:1005–1015PubMedGoogle Scholar
  25. Crespi CL, Penman BW (1997) Use of cDNA-expressed human cytochrome P450 enzymes to study potential drug–drug interactions. Adv Pharmacol 43:171–188PubMedGoogle Scholar
  26. Cresteil T, Monsarrat B, Paul Alvinerie P, Jean Marc Tréluyer JM, Isabel Vieira I, Wright M (1994) Taxol metabolism by human liver microsomes: identification of cytochrome P450 isozymes involved in its biotransformation. Cancer Res 54:386–392PubMedGoogle Scholar
  27. Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE (1992) The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 34:262–265PubMedGoogle Scholar
  28. Denton TT, Zhang X, Cashman JR (2005) 5-Substituted, 6-substituted, and unsubstituted 3-heteroaromatic pyridine analogues of nicotine as selective inhibitors of cytochrome P-450 2A6. J Med Chem 48:224–239PubMedGoogle Scholar
  29. Di Marco A, Cellucci A, Chaudhary A, Fonsi M, Laufer R (2007) High-throughput radiometric CYP2C19 inhibition assay using tritiated (S)-mephenytoin. Drug Metab Dispos 35:1737–1743PubMedGoogle Scholar
  30. Di L, Kerns EH, Li SQ, Carter GT (2007) Comparison of cytochrome P450 inhibition assays for drug discovery using human liver microsomes with LC-MS, rhCYP450 isozymes with fluorescence, and double cocktail with LC-MS. Int J Pharm 335:1–11PubMedGoogle Scholar
  31. Dierks EA, Stams KR, Lim HK, Cornelius G, Zhang H, Ball SE (2001) A method for the simultaneous evaluation of the activities of seven major human drug-metabolizing cytochrome P450s using an in vitro cocktail of probe substrates and fast gradient liquid chromatography tandem mass spectrometry. Drug Metab Dispos 29:23–29PubMedGoogle Scholar
  32. Donahue SR, Flockhart DA, Abernethy DR, Ko JW (1997) Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19. Clin Pharmacol Ther 62:572–577PubMedGoogle Scholar
  33. Draper AJ, Madan A, Parkinson A (1997) Inhibition of coumarin 7-hydroxylase activity in human liver microsomes. Arch Biochem Biophys 341:47–61PubMedGoogle Scholar
  34. Eagling VA, Tjia JF, Back DJ (1998) Differential specificity of cytochrome P450 inhibitors against probe substrates in human and rat liver microsomes. Br J Clin Pharmacol 45:107–114PubMedGoogle Scholar
  35. Emoto C, Murase S, Sawada Y, Jones BC, Iwasaki K (2003) In vitro inhibitory effect of 1-aminobenzotriazole on drug oxidations catalyzed by human cytochrome P450 enzymes: a comparison with SKF-525A and ketoconazole. Drug Metab Pharmacokinet 18:287–295PubMedGoogle Scholar
  36. Fairman DA, Collins C, Chapple S (2007) Progress curve analysis of CYP1A2 inhibition: a more informative approach to the assessment of mechanism–based inactivation? Drug Metab Dispos 35:2159–2165PubMedGoogle Scholar
  37. Faucette SR, Hawke RL, LeCluyse EL, Shord SS, Yan B, Laethem RM, Lindley CM (2000) Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos 28:1222–1230PubMedGoogle Scholar
  38. Fayer JL, Petullo DM, Ring BJ, Wrighton SA, Ruterbories KJ (2001) A novel testosterone 6 beta-hydroxylase activity assay for the study of CYP3A-mediated metabolism, inhibition, and induction in vitro. Pharmacol Toxicol Methods 46:117–123Google Scholar
  39. FDA (2006) Guidance for industry: drug interaction studies–study, design, data analysis, and implication for dosing and labeling. Accessed on 10 January 2011
  40. Finnström N, Bjelfman C, Söderström TG, Smith G, Egevad L, Norlén BJ, Wolf CR, Rane (2001) Detection of cytochrome P450 mRNA transcripts in prostate samples by RT-PCR. Eur J Clin Invest 31:880–886Google Scholar
  41. Fischer V, Johanson L, Heitz F, Tullman R, Graham E, Baldeck JP, Robinson WT (1999) The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: effect on human cytochrome P-450 and implications for metabolic drug interactions. Drug Metab Dispos 27:410–416PubMedGoogle Scholar
  42. Foti RS, Wahlstrom JL (2008) CYP2C19 inhibition: the impact of substrate probe selection on in vitro inhibition profiles. Drug Metab Dispos 36:523–528PubMedGoogle Scholar
  43. Fujino H, Yamada I, Shimada S, Hirano M, Tsunenari Y, Kojima J (2003) Interaction between fibrates and statins—metabolic interactions with gemfibrozil. Drug Metabol Drug Interact 19:161–176PubMedGoogle Scholar
  44. Fukami T, Nakajima M, Sakai H, Katoh M, Yokoi T (2007) CYP2A13 metabolizes the substrates of human CYP1A2, phenacetin, and theophylline. Drug Metab Dispos 35:335–339PubMedGoogle Scholar
  45. Galetin A, Clarke SE, Houston JB (2002) Quinidine and haloperidol as modifiers of CYP3A4 activity: multisite kinetic model approach. Drug Metab Dispos 30:1512–1522PubMedGoogle Scholar
  46. Gentile DM, Verhoeven CH, Shimada T, Back DJ (1998) The role of CYP2C in the in vitro bioactivation of the contraceptive steroid desogestrel. J Pharmacol Exp Ther 287:975–982PubMedGoogle Scholar
  47. Gervasini G, Martínez C, Agúndez JA, García-Gamito FJ, Benítez J (2001) Inhibition of cytochrome P450 2C9 activity in vitro by 5-hydroxytryptamine and adrenaline. Pharmacogenetics 11:29–37PubMedGoogle Scholar
  48. Gibbs MA, Thummel KE, Shen DD, Kunze KL (1999) Inhibition of cytochrome P–450 3A (CYP3A) in human intestinal and liver microsomes: comparison of K i values and impact of CYP3A5 expression. Drug Metab Dispos 27:180–187PubMedGoogle Scholar
  49. Guengerich FP (2005) Human cytochrome P450 enzymes. In: Ortiz de Montellano PR (ed) Cytochrome P450: structure, mechanism, and biochemistry, 3rd edn. Kluwer/Plenum Publishers, New York 382Google Scholar
  50. Guengerich FP (2006) Cytochrome P450s and Other Enzymes in Drug Metabolism and Toxicity. AAPS J 8:E101–E111PubMedGoogle Scholar
  51. Ha-Duong NT, Dijols S, Macherey AC, Dansette PM, Mansuy D (2001) Inhibition by ticlopidine and its derivatives of human liver cytochrome p450. Mechanism-based inactivation of CYP 2C19 by ticlopidine. Adv Exp Med Biol 500:145–148PubMedGoogle Scholar
  52. Hall SD, Guengerich FP, Branch RA, Wilkinson GR (1987) Characterization and inhibition of mephenytoin 4-hydroxylase activity in human liver microsomes. J Pharmacol Exp Ther 240:216–222PubMedGoogle Scholar
  53. Hemeryck A, De Vriendt C, Belpaire FM (1999) Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes. Eur J Clin Pharmacol 54:947–951PubMedGoogle Scholar
  54. Hermans JJ, Thijssen HH (1993) Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics. Br J Pharmacol 110:482–490PubMedGoogle Scholar
  55. Hesse LM, Venkatakrishnan K, Court MH, von Moltke LL, Duan SX, Shader RI, Greenblatt DJ (2000) CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos 28:1176–1183PubMedGoogle Scholar
  56. Higashi E, Nakajima M, Katoh M, Tokudome S, Yokoi T (2007) Inhibitory effects of neurotransmitters and steroids on human CYP2A6. Drug Metab Dispos 35:508–514PubMedGoogle Scholar
  57. Hiroi T, Kishimoto W, Chow T, Imaoka S, Igarashi T, Funae Y (2001) Progesterone oxidation by cytochrome P450 2D isoforms in the brain. Endocrinology 142:3901–3908PubMedGoogle Scholar
  58. Hirota N, Ito K, Iwatsubo T, Green CE, Tyson CA, Shimada N, Suzuki H, Sugiyama Y (2001) In vitro/in vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humans. Biopharm Drug Dispos 22:53–71PubMedGoogle Scholar
  59. Hodges VM, Molloy GY, Wickramasinghe SN (2000) Demonstration of mRNA for five species of cytochrome P450 in human bone marrow, bone marrow-derived macrophages and human haemopoietic cell lines. Br J Haematol 108:151–156PubMedGoogle Scholar
  60. Hruska MW, Amico JA, Langaee TY, Ferrell RE, Fitzgerald SM, Frye RF (2005) The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects. Br J Clin Pharmacol 59:70–79PubMedGoogle Scholar
  61. Hukkanen J, Jacob P 3rd, Benowitz NL (2005) Metabolism and disposition kinetics of nicotine. Pharmacol Rev 57:79–115PubMedGoogle Scholar
  62. Iribarne C, Picart D, Dréano Y, Berthou F (1998) In vitro interactions between fluoxetine or fluvoxamine and methadone or buprenorphine. Fundam Clin Pharmacol 12:194–199PubMedGoogle Scholar
  63. Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT (2005) Metabolism of repaglinide by CYP2C8 and CYP3A4 in vitro: effect of fibrates and rifampicin. Basic Clin Pharmacol Toxicol 97:249–256PubMedGoogle Scholar
  64. Katoh M, Nakajima M, Shimada N, Yamazaki H, Yokoi T (2000) Inhibition of human cytochrome P450 enzymes by 1, 4–dihydropyridine calcium antagonists: prediction of in vivo drug–drug interactions. Eur J Clin Pharmacol 55(11–12):843–852PubMedGoogle Scholar
  65. Kenworthy KE, Bloomer JC, Clarke SE, Houston JB (1999) CYP3A4 drug interactions: correlation of 10 in vitro probe substrates. Br J Clin Pharmacol 48:716–727PubMedGoogle Scholar
  66. Kerry NL, Somogyi AA, Bochner F, Mikus G (1994) The role of CYP2D6 in primary and secondary oxidative metabolism of dextromethorphan: in vitro studies using human liver microsomes. Br J Clin Pharmacol 38:243–248PubMedGoogle Scholar
  67. Ko JW, Desta Z, Soukhova NV, Tracy T, Flockhart DA (2000) In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6. Br J Clin Pharmacol 49:343–351PubMedGoogle Scholar
  68. Kobayashi K, Yamamoto T, Chiba K, Tani M, Ishizaki T, Kuroiwa Y (1995) The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4′-hydroxylase activity in human liver microsomes. Br J Clin Pharmacol 40:481–485PubMedGoogle Scholar
  69. Koenigs LL, Peter RM, Thompson SJ, Rettie AE, Trager WF (1997) Mechanism-based inactivation of human liver cytochrome P450 2A6 by 8-methoxypsoralen. Drug Metab Dispos 25:1407–1415PubMedGoogle Scholar
  70. Komatsu K, Ito K, Nakajima Y, Kanamitsu S, Imaoka S, Funae Y, Green CE, Tyson CA, Shimada N, Sugiyama Y (2000) Prediction of in vivo drug–drug interactions between tolbutamide and various sulfonamides in humans based on in vitro experiments. Drug Metab Dispos 28:475–481PubMedGoogle Scholar
  71. Kronbach T, Mathys D, Umeno M, Gonzalez FJ, Meyer UA (1989) Oxidation of midazolam and triazolam by human liver cytochrome P450IIIA4. Mol Pharmacol 36:89–96PubMedGoogle Scholar
  72. Kumar V, Rock DA, Warren CJ, Tracy TS, Wahlstrom JL (2006) Enzyme source effects on CYP2C9 kinetics and inhibition. Drug Metab Dispos 34:1903–1908PubMedGoogle Scholar
  73. Kunze KL, Trager WF (1993) Isoform-selective mechanism-based inhibition of human cytochrome P450 1A2 by furafylline. Chem Res Toxicol 6:649–656PubMedGoogle Scholar
  74. Kunze KL, Eddy AC, Gibaldi M, Trager WF (1991) Metabolic enantiomeric interactions: the inhibition of human (S)-warfarin-7-hydroxylase by (R)-warfarin. Chirality 3:24–29PubMedGoogle Scholar
  75. Lavhekar SS, Bhopale AK, Lohade AA, Coutinho EC, Iyer KR (2007) Determination of microsomal CYP2A6 activity by high performance liquid chromatography. Indian J Pharm Sci 69:448–451Google Scholar
  76. Le Gal A, Dréano Y, Lucas D, Berthou F (2003) Diversity of selective environmental substrates for human cytochrome P450 2A6: alkoxyethers, nicotine, coumarin, N-nitrosodiethylamine, and N-nitrosobenzylmethylamine. Toxicol Lett 144:77–91PubMedGoogle Scholar
  77. Leemann T, Transon C, Dayer P (1993) Cytochrome P450 TB (CYP2C): a major monooxygenase catalyzing diclofenac 4′-hydroxylation in human liver. Life Sci 52:29–34PubMedGoogle Scholar
  78. Li XQ, Björkman A, Andersson TB, Ridderström M, Masimirembwa CM (2002) Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. Pharmacol Exp Ther 300:399–407Google Scholar
  79. Li XQ, Andersson TB, Ahlström M, Weidolf L (2004) Comparison of inhibitory effects of the proton pump–inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos 32:821–827PubMedGoogle Scholar
  80. Lu AY, Wang RW, Lin JH (2003) Cytochrome P450 in vitro reaction phenotyping: a re-evaluation of approaches used for P450 isoform identification. Drug Metab Dispos 31:345–350PubMedGoogle Scholar
  81. Lucas D, Ferrara R, Gonzalez E, Bodenez P, Albores A, Manno M, Berthou F (1999) Chlorzoxazone, a selective probe for phenotyping CYP2E1 in humans. Pharmacogenetics 9:377–388PubMedGoogle Scholar
  82. Lukkari E, Taavitsainen P, Juhakoski A, Pelkonen O (1998) Cytochrome P450 specificity of metabolism and interactions of oxybutynin in human liver microsomes. Pharmacol Toxicol 82:161–166PubMedGoogle Scholar
  83. Ma B, Prueksaritanont T, Lin JH (2000) Drug interactions with calcium channel blockers: possible involvement of metabolite–intermediate complexation with CYP3A. Drug Metab Dispos 28:125–130PubMedGoogle Scholar
  84. Mäenpää J, Juvonen R, Raunio H, Rautio A, Pelkonen O (1994) Metabolic interactions of methoxsalen and coumarin in humans and mice. Biochem Pharmacol 48:1363–1369PubMedGoogle Scholar
  85. Mancy A, Dijols S, Poli S, Guengerich P, Mansuy D (1996) Interaction of sulfaphenazole derivatives with human liver cytochromes P450 2C: molecular origin of the specific inhibitory effects of sulfaphenazole on CYP 2C9 and consequences for the substrate binding site topology of CYP 2C9. Biochemistry 35:16205–16212PubMedGoogle Scholar
  86. Mankowski DC (1999) The role of CYP2C19 in the metabolism of (±) bufuralol, the prototypic substrate of CYP2D6. Drug Metab Dispos 27:1024–1028PubMedGoogle Scholar
  87. Margolis JM, Obach RS (2003) Impact of nonspecific binding to microsomes and phospholipid on the inhibition of cytochrome P4502D6: implications for relating in vitro inhibition data to in vivo drug interactions. Drug Metab Dispos 31:606–611PubMedGoogle Scholar
  88. Marill J, Capron CC, Idres N, Chabot GG (2002) Human cytochrome P450s involved in the metabolism of 9-cis- and 13-cis-retinoic acids. Biochem Pharmacol 63:933–943PubMedGoogle Scholar
  89. Masimirembwa CM, Otter C, Berg M, Jönsson M, Leidvik B, Jonsson E, Johansson T, Bäckman A, Edlund A, Andersson TB (1999) Heterologous expression and kinetic characterization of human cytochromes P-450: validation of a pharmaceutical tool for drug metabolism research. Drug Metab Dispos 27:1117–1122PubMedGoogle Scholar
  90. Matsumoto S, Hirama T, Matsubara T, Nagata K, Yamazoe Y (2002) Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, Astemizole. Drug Metab Dispos 30:1240–1245PubMedGoogle Scholar
  91. McGinnity DF, Tucker J, Trigg S, Riley RJ (2005) Prediction of CYP2C9-mediated drug–drug interactions: a comparison using data from recombinant enzymes and human hepatocytes. Drug Metab Dispos 33:1700–1707PubMedGoogle Scholar
  92. McGinnity DF, Berry AJ, Kenny JR, Grime K, Riley RJ (2006) Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes. Drug Metab Dispos 34:1291–1300PubMedGoogle Scholar
  93. McKillop D, Wild MJ, Butters CJ, Simcock C (1998) Effects of propofol on human hepatic microsomal cytochrome P450 activities. Xenobiotica 28:845–853PubMedGoogle Scholar
  94. McKinnon RA, Hall PM, Quattrochi LC, Tukey RH, McManus ME (1991) Localization of CYP1A1 and CYP1A2 mRNA in normal liver and hepatocellular carcinoma by in situ hybridization. Hepatology 14:848–856PubMedGoogle Scholar
  95. Messina ES, Tyndale RF, Sellers EM (1997) A major role for CYP2A6 in nicotine C-oxidation by human liver microsomes. J Pharmacol Exp Ther 282:1608–1614PubMedGoogle Scholar
  96. Miners JO, Birkett DJ (1996a) The use of caffeine as a metabolic probe for human drug metabolizing enzymes. Gen Pharmacol 27:245–249PubMedGoogle Scholar
  97. Miners JO, Birkett DJ (1996b) Use of tolbutamide as a substrate probe for human hepatic cytochrome P450 2C9. Methods Enzymol 272:139–145PubMedGoogle Scholar
  98. Monsarrat B, Royer I, Wright M, Cresteil T (1997) Biotransformation of taxoids by human cytochromes P450: structure-activity relationship. Bull Cancer 84:125–133PubMedGoogle Scholar
  99. Moody GC, Griffin SJ, Mather AN, McGinnity DF, Riley RJ (1999) Fully automated analysis of activities catalysed by the major human liver cytochrome P450 (CYP) enzymes: assessment of human CYP inhibition potential. Xenobiotica 29:53–75PubMedGoogle Scholar
  100. Nadin L, Murray M (1999) Participation of CYP2C8 in retinoic acid 4-hydroxylation in human hepatic microsomes. Biochem Pharmacol 58:1201–1208PubMedGoogle Scholar
  101. Nakajima M, Yamamoto T, Nunoya K, Yokoi T, Nagashima K, Inoue K, Funae Y, Shimada N, Kamataki T, Kuroiwa Y (1996) Characterization of CYP2A6 involved in 3′-hydroxylation of cotinine in human liver microsomes. J Pharmacol Exp Ther 277:1010–1015PubMedGoogle Scholar
  102. Nakajima M, Itoh M, Sakai H, Fukami T, Katoh M, Yamazaki H, Kadlubar FF, Imaoka S, Funae Y, Yokoi T (2006) CYP2A13 expressed in human bladder metabolically activates 4-aminobiphenyl. Int J Cancer 119:2520–2526PubMedGoogle Scholar
  103. Nakamura K, Yokoi T, Inoue K, Shimada N, Ohashi N, Kume T, Kamataki T (1996) CYP2D6 is the principal cytochrome P450 responsible for metabolism of the histamine H1 antagonist promethazine in human liver microsomes. Pharmacogenetics 6:449–457PubMedGoogle Scholar
  104. Nelson MH, Birnbaum AK, Remmel RP (2001) Inhibition of phenytoin hydroxylation in human liver microsomes by several selective serotonin re-uptake inhibitors. Epilepsy Res 44:71–82PubMedGoogle Scholar
  105. Newton DJ, Wang RW, Lu AYH (1995) Cytochrome P450 inhibitors: evaluation of specificities in the in vitro metabolism of therapeutic agents by human liver microsomes. Drug Metab Dispos 23:154–158PubMedGoogle Scholar
  106. Nielsen KK, Flinois JP, Beaune P, Brøsen K (1996) The biotransformation of clomipramine in vitro, identification of the cytochrome P450s responsible for the separate metabolic pathways. J Pharmacol Exp Ther 277:1659–1664PubMedGoogle Scholar
  107. Niwa T, Shiraga T, Yamasaki S, Ishibashi K, Ohno Y, Kagayama A (2003) In vitro activation of 7-benzyloxyresorufin O-debenzylation and nifedipine oxidation in human liver microsomes. Xenobiotica 33:717–729PubMedGoogle Scholar
  108. Obach RS (2000) Inhibition of human cytochrome P450 enzymes by constituents of St. John’s Wort, an herbal preparation used in the treatment of depression. J Pharmacol Exp Ther 294:88–95PubMedGoogle Scholar
  109. Ogilvie BW, Zhang D, Li W, Rodrigues D, Gipson AE, Holsapple J, Toren P, Parkinson A (2006) Glucuronidation converts gemfibrozil to a potent, metabolism-dependent inhibitor of CYP2C8: implications for drug–drug interactions. Drug Metab Dispos 34:191–197PubMedGoogle Scholar
  110. Olesen OV, Linnet K (2000) Fluvoxamine–clozapine drug interaction: inhibition in vitro of five cytochrome P450 isoforms involved in clozapine metabolism. J Clin Psychopharmacol 20:35–42PubMedGoogle Scholar
  111. Ong CE, Coulter S, Birkett DJ, Bhasker CR, Miners JO (2000) The xenobiotic inhibitor profile of cytochrome P4502C8. Br J Clin Pharmacol 50:573–580PubMedGoogle Scholar
  112. Otton SV, Wu D, Joffe RT, Cheung SW, Sellers EM (1993) Inhibition by fluoxetine of cytochrome P450 2D6 activity. Clin Pharmacol Ther 53:401–409PubMedGoogle Scholar
  113. Otton SV, Ball SE, Cheung SW, Inaba T, Rudolph RL, Sellers EM (1996) Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br J Clin Pharmacol 41:149–156PubMedGoogle Scholar
  114. Pan LP, Wijnant P, De Vriendt C, Rosseel MT, Belpaire FM (1997) Characterization of the cytochrome P450 isoenzymes involved in the in vitro N-dealkylation of haloperidol. Br J Clin Pharmacol 44:557–564PubMedGoogle Scholar
  115. Pelkonen O, Rautioa A, Raunioa H, Pasanen M (2000) CYP2A6: a human coumarin 7-hydroxylase. Toxicology 144:139–147PubMedGoogle Scholar
  116. Perloff MD, von Moltke LL, Court MH, Kotegawa T, Shader RI, Greenblatt DJ (2000) Midazolam and triazolam biotransformation in mouse and human liver microsomes: relative contribution of CYP3A and CYP2C isoforms. J Pharmacol Exp Ther 292:618–628PubMedGoogle Scholar
  117. Perloff ES, Mason AK, Dehal SS, Blanchard AP, Morgan L, Ho T, Dandeneau A, Crocker RM, Chandler CM, Boily N, Crespi CL, Stresser DM (2009) Validation of cytochrome P450 time-dependent inhibition assays: a two-time point IC50 shift approach facilitates kinact assay design. Xenobiotica 39:99–112PubMedGoogle Scholar
  118. Polasek TM, Miners JO (2006) Quantitative prediction of macrolide drug–drug interaction potential from in vitro studies using testosterone as the human cytochrome P4503A substrate. Eur J Clin Pharmacol 62:203–208PubMedGoogle Scholar
  119. Prueksaritanont T, Gorham LM, Ma B, Liu L, Yu X, Zhao JJ, Slaughter DE, Arison BH, Vyas KP (1997) In vitro metabolism of simvastatin in humans [SBT] identification of metabolizing enzymes and effect of the drug on hepatic P450s. Drug Metab Dispos 25:1191–1199PubMedGoogle Scholar
  120. Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH (2002) Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos 30:1280–1287PubMedGoogle Scholar
  121. Racha JK, Rettie AE, Kunze KL (1998) Mechanism-based inactivation of human cytochrome P450 1A2 by furafylline: detection of a 1:1 adduct to protein and evidence for the formation of a novel imidazomethide intermediate. Biochemistry 37:7407–7419PubMedGoogle Scholar
  122. Rahman A, Korzekwa KR, Grogan J, Gonzalez FJ, Harris JW (1994) Selective biotransformation of taxol to 6 alpha-hydroxytaxol by human cytochrome P450 2C8. Cancer Res 54:5543–5546PubMedGoogle Scholar
  123. Rasmussen BB, Nielsen TL, Brøsen K (1998) Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro. Eur J Clin Pharmacol 54(9–10):735–740PubMedGoogle Scholar
  124. Rendic S (2002) Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev 34:83–448PubMedGoogle Scholar
  125. Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T, Gelboin HV, Gonzalez FJ, Trager WF (1992) Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 5:54–59PubMedGoogle Scholar
  126. Richter T, Mürdter TE, Heinkele G, Pleiss J, Tatzel S, Schwab M, Eichelbaum M, Zanger UM (2004) Potent mechanism–based inhibition of human CYP2B6 by clopidogrel and ticlopidine. J Pharmacol Exp Ther 308:189–197PubMedGoogle Scholar
  127. Ring BJ, Binkley SN, Vandenbranden M, Wrighton SA (1996) In vitro interaction of the antipsychotic agent olanzapine with human cytochromes P450 CYP2C9, CYP2C19, CYP2D6 and CYP3A. Br J Clin Pharmacol 41:181–186PubMedGoogle Scholar
  128. Rochat B, Morsman JM, Murray GI, Figg WD, McLeod HL (2001) Human CYP1B1 and anticancer agent metabolism: mechanism for tumor-specific drug inactivation? J Pharmacol Exp Ther 296:537–541PubMedGoogle Scholar
  129. Rodrigues AD, Surber BW, Yao Y, Wong SL, Roberts EM (1997) [O-ethyl 14C]phenacetin O-deethylase activity in human liver microsomes. Drug Metab Dispos 25:1097–1100PubMedGoogle Scholar
  130. Sahi J, Black CB, Hamilton GA, Zheng X, Jolley S, Rose KA, Gilbert D, LeCluyse EL, Sinz MW (2003) Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition. Drug Metab Dispos 31:439–446PubMedGoogle Scholar
  131. Sai Y, Dai R, Yang TJ, Krausz KW, Gonzalez FJ, Gelboin HV, Shou M (2000) Assessment of specificity of eight chemical inhibitors using cDNA-expressed cytochromes P450. Xenobiotica 30:327–343PubMedGoogle Scholar
  132. Salsali M, Holt A, Baker GB (2004) Inhibitory effects of the monoamine oxidase inhibitor tranylcypromine on the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP2D6. Cell Mol Neurobiol 24:63–76PubMedGoogle Scholar
  133. Schmider J, Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI (1995) N-demethylation of amitriptyline in vitro: role of cytochrome P-450 3A (CYP3A) isoforms and effect of metabolic inhibitors. J Pharmacol Exp Ther 275:592–597PubMedGoogle Scholar
  134. Schmider J, Greenblatt DJ, Fogelman SM, von Moltke LL, Shader RI (1997) Metabolism of dextromethorphan in vitro: involvement of cytochromes P450 2D6 and 3A3/4, with a possible role of 2E1. Biopharm Drug Dispos 18:227–240PubMedGoogle Scholar
  135. Schwarz D, Kisselev P, Roots I (2005) CYP1A1 genotype-selective inhibition of benzo[a]pyrene activation by quercetin. Eur J Cancer 41:151–158PubMedGoogle Scholar
  136. Schweikl H, Taylor JA, Kitareewan S, Linko P, Nagorney D, Goldstein JA (1993) Expression of CYP1A1 and CYP1A2 genes in human liver. Pharmacogenetics 3:239–249PubMedGoogle Scholar
  137. Senda C, Kishimoto W, Sakai K, Nagakura A, Igarashi T (1997) Identification of human cytochrome P450 isoforms involved in the metabolism of brotizolam. Xenobiotica 27:913–922PubMedGoogle Scholar
  138. Shou M, Lu AY (2009) Antibodies as a probe in cytochrome P450 research. Drug Metab Dispos 37:925–931PubMedGoogle Scholar
  139. Skjelbo E, Brøsen K (1992) Inhibitors of imipramine metabolism by human liver microsomes. Br J Clin Pharmacol 34:256–261PubMedGoogle Scholar
  140. Soars MG, Grime K, Riley RJ (2006) Comparative analysis of substrate and inhibitor interactions with CYP3A4 and CYP3A5. Xenobiotica 36:287–299PubMedGoogle Scholar
  141. Stevens JC, White RB, Hsu SH, Martinet M (1997) Human liver CYP2B6-catalyzed hydroxylation of RP 73401. J Pharmacol Exp Ther 282:1389–1395PubMedGoogle Scholar
  142. Stresser DM, Broudy MI, Ho T, Cargill CE, Blanchard AP, Sharma R, Dandeneau AA, Goodwin JJ, Turner SD, Erve JC, Patten CJ, Dehal SS, Crespi CL (2004) Highly selective inhibition of human CYP3Aa in vitro by azamulin and evidence that inhibition is irreversible. Drug Metab Dispos 32:105–112PubMedGoogle Scholar
  143. Suzuki H, Kneller MB, Haining RL, Trager WF, Rettie AE (2002) (+)-N-3-Benzyl-nirvanol and (-)-N-3-benzyl-phenobarbital: new potent and selective in vitro inhibitors of CYP2C19. Drug Metab Dispos 30:235–239PubMedGoogle Scholar
  144. Taavitsainen P, Anttila M, Nyman L, Karnani H, Salonen JS, Pelkonen O (2000) Selegiline metabolism and cytochrome P450 enzymes: in vitro study in human liver microsomes. Pharmacol Toxicol 86:215–221PubMedGoogle Scholar
  145. Taavitsainen P, Juvonen R, Pelkonen O (2001) In vitro inhibition of cytochrome P450 enzymes in human liver microsomes by a potent CYP2A6 inhibitor, trans-2-phenylcyclopropylamine (tranylcypromine), and its nonamine analog, cyclopropylbenzene. Drug Metab Dispos 29:217–222PubMedGoogle Scholar
  146. Tang BK, Kalow W (1996) Assays for CYP1A2 by testing in vivo metabolism of caffeine in humans. Methods Enzymol 272:124–131PubMedGoogle Scholar
  147. Tang W, Wang RW, Lu AY (2005) Utility of recombinant cytochrome p450 enzymes: a drug metabolism perspective. Curr Drug Metab 6:503–517PubMedGoogle Scholar
  148. Testino SA Jr, Patonay G (2003) High-throughput inhibition screening of major human cytochrome P450 enzymes using an in vitro cocktail and liquid chromatography–tandem mass spectrometry. J Pharm Biomed Anal 30:1459–1467PubMedGoogle Scholar
  149. Tornio A, Niemi M, Neuvonen PJ, Backman JT (2008) Trimethoprim and the CYP2C8*3 allele have opposite effects on the pharmacokinetics of pioglitazone. Drug Metab Dispos 36:73–80PubMedGoogle Scholar
  150. Totah RA, Sheffels P, Roberts T, Whittington D, Thummel K, Kharasch ED (2008) Role of CYP2B6 in stereoselective human methadone metabolism. Anesthesiology 108:351–352Google Scholar
  151. Tracy TS, Korzekwa KR, Gonzalez FJ, Wainer IW (1999) Cytochrome P450 isoforms involved in metabolism of the enantiomers of verapamil and norverapamil. Br J Clin Pharmacol 47:545–552PubMedGoogle Scholar
  152. Tran TH, von Moltke LL, Venkatakrishnan K, Granda BW, Gibb MA, Obach RS, Harmatz JS, Greenblatt DJ (2002) Microsomal protein concentration modifies the apparent inhibitory potency of CYP3A inhibitors. Drug Metab Dispos 30:1441–1445PubMedGoogle Scholar
  153. Tucker GT, Houston JB, Huang SM (2001) Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential-toward a consensus. Clin Pharmacol Ther 70:103–114PubMedGoogle Scholar
  154. Turpeinen M, Nieminen R, Juntunen T, Taavitsainen P, Raunio H, Pelkonen O (2004) Selective inhibition of CYP2B6-catalyzed bupropion hydroxylation in human liver microsomes in vitro. Drug Metab Dispos 32:626–631PubMedGoogle Scholar
  155. Turpeinen M, Raunio H, Pelkonen O (2006) The functional role of CYP2B6 in human drug metabolism: substrates and inhibitors in vitro, in vivo and in silico. Curr Drug Metab 7:705–714PubMedGoogle Scholar
  156. Venkatakrishnan K, von Moltke LL, Duan SX, Fleishaker JC, Shader RI, Greenblatt DJ (1998a) Kinetic characterization and identification of the enzymes responsible for the hepatic biotransformation of adinazolam and N-desmethyladinazolam in man. J Pharm Pharmacol 50:265–274PubMedGoogle Scholar
  157. Venkatakrishnan K, von Moltke LL, Greenblatt DJ (1998b) Human cytochromes P450 mediating phenacetin O-deethylation in vitro: validation of the high affinity component as an index of CYP1A2 activity. J Pharm Sci 87:1502–1507PubMedGoogle Scholar
  158. von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, Harmatz JS, Shader RI (1994a) Inhibitors of alprazolam metabolism in vitro: effect of serotonin-reuptake-inhibitor antidepressants, ketoconazole and quinidine. Br J Clin Pharmacol 38:23–31Google Scholar
  159. von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, Duan SX, Harmatz JS, Shader RI (1994b) 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 268:1278–1283Google Scholar
  160. von Moltke LL, Greenblatt DJ, Court MH, Duan SX, Harmatz JS, Shader RI (1995) Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J Clin Psychopharmacol 15:125–131Google Scholar
  161. von Moltke LL, Greenblatt DJ, Duan SX, Schmider J, Kudchadker L, Fogelman SM, Harmatz JS, Shader RI (1996a) Phenacetin O-deethylation by human liver microsomes in vitro: inhibition by chemical probes, SSRI antidepressants, nefazodone and venlafaxine. Psychopharmacology (Berl) 128:398–407Google Scholar
  162. von Moltke LL, Greenblatt DJ, Duan SX, Harmatz JS, Wright CE, Shader RI (1996b) 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 16:104–112Google Scholar
  163. von Moltke LL, Greenblatt DJ, Harmatz JS, Duan SX, Harrel LM, Cotreau-Bibbo MM, Pritchard GA, Wright CE, Shader RI (1996c) Triazolam biotransformation by human liver microsomes in vitro: effects of metabolic inhibitors and clinical confirmation of a predicted interaction with ketoconazole. J Pharmacol Exp Ther 276:370–379Google Scholar
  164. von Moltke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS, Shader RI (1996d) Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents. J Clin Pharmacol 36:783–791Google Scholar
  165. von Moltke LL, Duan SX, Greenblatt DJ, Fogelman SM, Schmider J, Harmatz JS, Shader RI (1997a) Venlafaxine and metabolites are very weak inhibitors of human cytochrome P450–3A isoforms. Biol Psychiatry 41:377–380Google Scholar
  166. von Moltke LL, Greenblatt DJ, Duan SX, Schmider J, Wright CE, Harmatz JS, Shader RI (1997b) Human cytochromes mediating N-demethylation of fluoxetine in vitro. Psychopharmacology (Berl) 132:402–407Google Scholar
  167. von Moltke LL, Greenblatt DJ, Grassi JM, Granda BW, Duan SX, Fogelman SM, Daily JP, Harmatz JS, Shader RI (1998) Protease inhibitors as inhibitors of human cytochromes P450: high risk associated with ritonavir. J Clin Pharmacol 38:106–111Google Scholar
  168. von Moltke LL, Greenblatt DJ, Granda BW, Grassi JM, Schmider J, Harmatz JS, Shader RI (1999) Nefazodone, meta-chlorophenylpiperazine, and their metabolites in vitro: cytochromes mediating transformation, and P450–3A4 inhibitory actions. Psychopharmacology (Berl) 145:113–122Google Scholar
  169. Walsky RL, Obach RS (2004) Validated assays for human cytochrome P450 activities. Drug Metab Dispos 32:647–660PubMedGoogle Scholar
  170. Walsky RL, Obach RS (2007) A comparison of 2-phenyl-2-(1-piperidinyl)propane (ppp), 1, 1′, 1′′-phosphinothioylidynetrisaziridine (thioTEPA), clopidogrel, and ticlopidine as selective inactivators of human cytochrome P450 2B6. Drug Metab Dispos 35:2053–2059PubMedGoogle Scholar
  171. Walsky RL, Obach RS, Gaman EA, Gleeson JP, Proctor WR (2005a) Selective inhibition of human cytochrome P4502C8 by montelukast. Drug Metab Dispos 33:413–418PubMedGoogle Scholar
  172. Walsky RL, Gaman EA, Obach RS (2005b) Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol 45:68–78PubMedGoogle Scholar
  173. Walsky RL, Astuccio AV, Obach RS (2006) Evaluation of 227 drugs for in vitro inhibition of cytochrome P450 2B6. J Clin Pharmacol 46:1426–1438PubMedGoogle Scholar
  174. Wandel C, Kim RB, Guengerich FP, Wood AJ (2000) Mibefradil is a P-glycoprotein substrate and a potent inhibitor of both P-glycoprotein and CYP3A in vitro. Drug Metab Dispos 28:895–898PubMedGoogle Scholar
  175. Wang H, Tompkins LM (2008) CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme. Curr Drug Metab 9:598–610PubMedGoogle Scholar
  176. Wang RW, Newton DJ, Scheri TD, Lu AY (1997) Human cytochrome P450 3A4-catalyzed testosterone 6 beta-hydroxylation and erythromycin N-demethylation. Competition during catalysis. Drug Metab Dispos 25:502–507PubMedGoogle Scholar
  177. Wang JS, Neuvonen M, Wen X, Backman JT, Neuvonen PJ (2002) Gemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes. Drug Metab Dispos 30:1352–1356PubMedGoogle Scholar
  178. Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, Desta Z (2003) The cytochrome P450 2B6 (CYP2B6) is the main catalyst of efavirenz primary and secondary metabolism: implication for HIV/AIDS therapy and utility of efavirenz as a substrate marker of CYP2B6 catalytic activity. J Pharmacol Exp Ther 306:287–300PubMedGoogle Scholar
  179. Wen X, Wang JS, Backman JT, Kivistö KT, Neuvonen PJ (2001) Gemfibrozil is a potent inhibitor of human cytochrome P450 2C9. Drug Metab Dispos 29:1359–1361PubMedGoogle Scholar
  180. Wen X, Wang JS, Backman JT, Laitila J, Neuvonen PJ (2002) Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9, respectively. Drug Metab Dispos 30:631–635PubMedGoogle Scholar
  181. Wienkers LC, Wurden CJ, Storch E, Kunze KL, Rettie AE, Trager WF (1996) Formation of (R)-8-hydroxywarfarin in human liver microsomes. A new metabolic marker for the (S)-mephenytoin hydroxylase, P4502C19. Drug Metab Dispos 24:610–614PubMedGoogle Scholar
  182. Williams JA, Susan I, Hurst SI, Bauman J, Jones BC, Hyland R, Gibbs JP, Obach RS, Ball SE (2003) Reaction phenotyping in drug discovery: moving forward with confidence? Curr Drug Metab 4:527–534PubMedGoogle Scholar
  183. Wrighton SA, Ring BJ (1994) Inhibition of human CYP3A catalyzed 1’-hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine, and nizatidine. Pharm Res 11:921–924PubMedGoogle Scholar
  184. Wrighton SA, Thummel KE (2000) CYP3A. In: Levy RH (ed) Metabolic drug interactions. Lippincott, Williams and Wilkins, Philadelphia, pp 115–133Google Scholar
  185. Yamazaki H, Shimada T (1997) Human liver cytochrome P450 enzymes involved in the 7-hydroxylation of R- and S-warfarin enantiomers. Biochem Pharmacol 54:1195–1203PubMedGoogle Scholar
  186. Yano JK, Denton TT, Cerny MA, Zhang X, Johnson EF, Cashman JR (2006) Synthetic inhibitors of cytochrome P-450 2A6: inhibitory activity, difference spectra, mechanism of inhibition, and protein cocrystallization. J Med Chem 49:6987–7001PubMedGoogle Scholar
  187. Yin H, Racha J, Li SY, Olejnik N, Satoh H, Moore D (2000) Automated high throughput human CYP isoform activity assay using SPE–LC/MS method: application in CYP inhibition evaluation. Xenobiotica 30:141–154PubMedGoogle Scholar
  188. Zanger UM, Eichelbaum M (2000) CYP2D6. In: Levy RH (ed) Metabolic drug interactions. Lippincott Williams and Wilkins, Philadelphia, pp 87–94Google Scholar
  189. Zhang Z, Fasco MJ, Huang Z, Guengerich FP, Kaminsky LS (1995) Human cytochromes P4501A1 and P4501A2: R-warfarin metabolism as a probe. Drug Metab Dispos 23:1339–1346PubMedGoogle Scholar
  190. Zhang W, Kilicarslan T, Tyndale RF, Sellers EM (2001) Evaluation of methoxsalen, tranylcypromine, and tryptamine as specific and selective CYP2A6 inhibitors in vitro. Drug Metab Dispos 29:897–902PubMedGoogle Scholar
  191. Zhao P, Kunze KL, Lee CA (2005) Evaluation of time-dependent inactivation of CYP3A in cryopreserved human hepatocytes. Drug Metab Dispos 33:853–861PubMedGoogle Scholar
  192. Zhou S, Paxton JW, Tingle MD, Kestell P (2000) Identification of the human liver cytochrome P450 isoenzyme responsible for the 6-methylhydroxylation of the novel anticancer drug 5, 6-dimethylxanthenone-4-acetic acid. Drug Metab Dispos 28:1449–1459PubMedGoogle Scholar
  193. Zou L, Harkey MR, Henderson GL (2002) Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity. Life Sci 71:1579–1589PubMedGoogle Scholar

Copyright information

© Springer-Verlag France 2011

Authors and Affiliations

  • Siamak Cyrus Khojasteh
    • 1
    Email author
  • Saileta Prabhu
    • 1
  • Jane R. Kenny
    • 1
  • Jason S. Halladay
    • 1
  • Anthony Y. H. Lu
    • 2
  1. 1.Genentech, IncSouth San FranciscoUSA
  2. 2.Department of Chemical BiologyErnest Mario College of Pharmacy, Rutgers UniversityPiscatawayUSA

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