In vitro-to-in vivo predictions of drugdrug interactions involving multiple reversible inhibitors

Expert Opinion on Drug Metabolism and Toxicology

Volumn 8, Issue 4, 2012, Pages 449-466

  Lutz, Justin D ^a   Isoherranen, Nina ^a  

^a UNIVERSITY OF WASHINGTON   (United States)

Author keywords

Cytochrome P450; Drugdrug interactions; in vitro to in vivo prediction; Inhibitory metabolites; Multiple inhibitors; Reversible inhibition

Indexed keywords

AMFEBUTAMONE; AMIODARONE; BUCOLOME; CIMETIDINE; CLOZAPINE; CYCLOSPORIN; CYTOCHROME P450; CYTOCHROME P450 INHIBITOR; DESIPRAMINE; FLUCONAZOLE; FLUINDOSTATIN; FLUOXETINE; FLUVOXAMINE; FURAFYLLINE; HALOPERIDOL; INDINAVIR; ITRACONAZOLE; KETOCONAZOLE; MIDAZOLAM; NICARDIPINE; OMEPRAZOLE; PAROXETINE; PRIMAQUINE; RADAFAXINE; RITONAVIR; SAQUINAVIR; SERTRALINE; TERFENADINE; UNINDEXED DRUG; WARFARIN;

AREA UNDER THE CURVE; CHEMICAL INTERACTION; COMPETITIVE INHIBITION; DRUG BINDING; FOOD AND DRUG ADMINISTRATION; IN VITRO STUDY; IN VIVO STUDY; LIVER CELL; LIVER MICROSOME; MAXIMUM PLASMA CONCENTRATION; REVIEW; SINGLE DRUG DOSE;

ALGORITHMS; ANIMALS; ANTIDEPRESSIVE AGENTS, SECOND-GENERATION; ANTIDEPRESSIVE AGENTS, TRICYCLIC; AREA UNDER CURVE; CYTOCHROME P-450 ENZYME SYSTEM; DESIPRAMINE; DRUG INTERACTIONS; ENZYME INHIBITORS; FLUOXETINE; FORECASTING; HUMANS; KINETICS; MODELS, STATISTICAL; PHARMACEUTICAL PREPARATIONS;

EID: 84858822506     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2012.667801     Document Type: Review

References (101)

1. Isoherranen N, Hachad H, Yeung CK, Levy RH. Qualitative analysis of the role of metabolites in inhibitory drug-drug interactions: Literature evaluation based on the metabolism and transport drug interaction database. Chem Res Toxicol 2009;22(2):294-8
2. Grimm SW, Einolf HJ, Hall SD, et al. The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: A perspective of the pharmaceutical research and manufacturers of America. Drug Metab Dispos 2009;37(7):1355-70 A useful review of in vitro-to-in vivo prediction of irreversible inhibition.
3. Obach RS, Walsky RL, Venkatakrishnan K. Mechanism-based inactivation of human cytochrome p450 enzymes and the prediction of drug-drug interactions. Drug Metab Dispos 2007;35(2):246-55
4. He M, Kunze KL, Trager WF. Inhibition of (S)-warfarin metabolism by sulfinpyrazone and its metabolites. Drug Metab Dispos 1995;23(6):659-63
5. Isoherranen N, Kunze KL, Allen KE, et al. Role of itraconazole metabolites in CYP3A4 inhibition. Drug Metab Dispos 2004;32(10):1121-31
6. Greenblatt DJ, Von Moltke LL, Schmider J, et al. Inhibition of human cytochrome P450-3A isoforms by fluoxetine and norfluoxetine: In vitro and in vivo studies. J Clin Pharmacol 1996;36(9):792-8
7. Hassan-Alin M, Andersson T, Niazi M, Rohss K. A pharmacokinetic study comparing single and repeated oral doses of 20 mg and 40 mg omeprazole and its two optical isomers, S-omeprazole (esomeprazole) and R-omeprazole, in healthy subjects. Eur J Clin Pharmacol 2005;60(11):779-84
8. Li XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos 2004;32(8):821-7
9. Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet 2002;41(14):1195-211
10. Niemi M, Backman JT, Neuvonen M, Neuvonen PJ. Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: Potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 2003;46(3):347-51 A clinical study highlighting the risk of multiple simultaneously administered inhibitors.
11. Reese MJ, Wurm RM, Muir KT, et al. An in vitro mechanistic study to elucidate the desipramine/bupropion clinical drug-drug interaction. Drug Metab Dispos 2008;36(7):1198-201 Good example of a multiple inhibitor system where the metabolites play the most important role to inhibition.
12. Templeton I, Peng CC, Thummel KE, et al. Accurate prediction of dose-dependent CYP3A4 inhibition by itraconazole and its metabolites from in vitro inhibition data. Clin Pharmacol Ther 2010;88(4):499-505
13. Yeung CK, Fujioka Y, Hachad H, et al. Are circulating metabolites important in drug-drug interactions? Quantitative analysis of risk prediction and inhibitory potency. Clin Pharmacol Ther 2010;89(1):105-13 . Important review and prediction of circulating inhibitory metabolites.
14. Hinton L, Galetin A, Houston J. Multiple inhibition mechanisms and prediction of drug-drug interactions: Status of metabolism and transporter models as exemplified by gemfibrozil-drug interactions. Pharm Res 2008;25(5):1063-74 Study of a complex multiple inhibitor system with both reversible and irreversible inhibition as well as transport aspects.
15. Ohyama K, Nakajima M, Suzuki M, et al. Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities: Prediction of in vivo drug interactions. Br J Clin Pharmacol 2000;49(3):244-53
16. Zhang X, Jones DR, Hall SD. Prediction of the effect of erythromycin, diltiazem, and their metabolites, alone and in combination, on CYP3A4 inhibition. Drug Metab Dispos 2009;37(1):150-60 Good study of different models to predict simultaneous reversible and irreversible inhibition.
17. Wang YH, Jones DR, Hall SD. Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. Drug Metab Dispos 2004;32(2):259-66
18. Rowland Yeo K, Jamei M, Yang J, et al. Physiologically based mechanistic modelling to predict complex drug-drug interactions involving simultaneous competitive and time-dependent enzyme inhibition by parent compound and its metabolite in both liver and gut - the effect of diltiazem on the time-course of exposure to triazolam. Eur J Pharm Sci 2010;39(5):298-309
19. Segel IH. Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems. 3rd edition. Wiley-Interscience; New York: 1993
20. Venkatakrishnan K, von Moltke LL, Obach RS, Greenblatt DJ. Drug metabolism and drug interactions: Application and clinical value of in vitro models. Curr Drug Metab 2003;4(5):423-59
21. Rostami-Hodjegan A, Tucker G. 'In silico' simulations to assess the 'in vivo' consequences of 'in vitro' metabolic drug-drug interactions. Drug Discov Today 2004;1(4):441-8 . Initial proposal of the product rule for predicting multiple inhibitors with different reversible inhibition mechanisms.
22. Huang W, Lin YS, McConn DJ, et al. Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab Dispos 2004;32(12):1434-45
23. Kumar V, Wahlstrom JL, Rock DA, et al. CYP2C9 inhibition: Impact of probe selection and pharmacogenetics on in vitro inhibition profiles. Drug Metab Dispos 2006;34(12):1966-75
24. Galetin A, Clarke SE, Houston JB. Multisite kinetic analysis of interactions between prototypical CYP3A4 subgroup substrates: Midazolam, testosterone, and nifedipine. Drug Metab Dispos 2003;31(9):1108-16
25. Rowland M, Tozer TN. Clinical Pharmacokinetics: Concepts and Applications. 3rd edition. Lippincott, Williams and Wilkins; Philadelphia: 1995
26. Takahashi H, Kashima T, Kimura S, et al. Pharmacokinetic interaction between warfarin and a uricosuric agent, bucolome: Application of in vitro approaches to predicting in vivo reduction of (S)-warfarin clearance. Drug Metab Dispos 1999;27(10):1179-86
27. Ito K, Hallifax D, Obach RS, Houston JB. Impact of parallel pathways of drug elimination and multiple cytochrome P450 involvement on drug-drug interactions: CYP2D6 paradigm. Drug Metab Dispos 2005;33:837-44
28. Brown HS, Ito K, Galetin A, Houston JB. Prediction of in vivo drug-drug interactions from in vitro data: Impact of incorporating parallel pathways of drug elimination and inhibitor absorption rate constant. Br J Clin Pharmacol 2005;60(5):508-18 Good study of the effects of incorporating parallel metabolic pathways and bioavailability into DDI prediction models.
29. Rane A, Wilkinson GR, Shand DG. Prediction of hepatic extraction ratio from in vitro measurement of intrinsic clearance. J Pharmacol Exp Ther 1977;200(2):420-4
30. Obach RS. Predicting drug-drug interactions from in vitro drug metabolism data: Challenges and recent advances. Curr Opin Drug Discov Devel 2009;12(1):81-9 . Excellent reference on in vitro-to-in vivo prediction of DDIs.
31. Einolf HJ. Comparison of different approaches to predict metabolic drug-drug interactions. Xenobiotica 2007;37(10-11):1257-94
32. Shu Y, Wang L-S, Xu Z-H, et al. 5-hydroxylation of omeprazole by human liver microsomal fractions from Chinese populations related to CYP2C19 gene dose and individual ethnicity. J Pharmacol Exp Ther 2000;295(2):844-51
33. Rasmussen BB, Maenpaa J, Pelkonen O, et al. Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: Potent inhibition by fluvoxamine. Br J Clin Pharmacol 1995;39(2):151-9
34. Mendes P. Biochemistry by numbers: Simulation of biochemical pathways with Gepasi 3. Trends Biochem Sci 1997;22(9):361-3
35. Belpaire FM, Wijnant P, Temmerman A, et al. The oxidative metabolism of metoprolol in human liver microsomes: Inhibition by the selective serotonin reuptake inhibitors. Eur J Clin Pharmacol 1998;54(3):261-4
36. Stevens JC, Wrighton SA. Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. J Pharmacol Exp Ther 1993;266(2):964-71 Demonstration of significant stereoselectivity in P450 inhibition.
37. Bergstrom RF, Peyton AL, Lemberger L. Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction. Clin Pharmacol Ther 1992;51(3):239-48
38. Jannuzzi G, Gatti G, Magni P, et al. Plasma concentrations of the enantiomers of fluoxetine and norfluoxetine: Sources of variability and preliminary observations on relations with clinical response. Ther Drug Monit 2002;24(5):616-27
39. Obach RS, Walsky RL, Venkatakrishnan K, et al. In vitro cytochrome P450 inhibition data and the prediction of drug-drug interactions: Qualitative relationships, quantitative predictions, and the rank-order approach. Clin Pharmacol Ther 2005;78(6):582-92
40. Kanamitsu S, Ito K, Sugiyama Y. Quantitative prediction of in vivo drug-drug interactions from in vitro data based on physiological pharmacokinetics: Use of maximum unbound concentration of inhibitor at the inlet to the liver. Pharm Res 2000;17(3):336-43
41. Margolis JM, Obach RS. 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 2003;31(5):606-11 An interesting study of the use of in vitro fraction unbound values in DDI prediction.
42. Chien JY, Lucksiri A, Ernest CS II, et al. Stochastic prediction of CYP3A-mediated inhibition of midazolam clearance by ketoconazole. Drug Metab Dispos 2006;34(7):1208-19
43. Guest EJ, Rowland-Yeo K, Rostami-Hodjegan A, et al. Assessment of algorithms for predicting drug-drug interactions via inhibition mechanisms: Comparison of dynamic and static models. Br J Clin Pharmacol 2011;71(1):72-87 An interesting study comparing the predictive ability of static versus PBPK models.
44. Kunze KL, Eddy AC, Gibaldi M, Trager WF. Metabolic enantiomeric interactions: The inhibition of human (S)-warfarin-7-hydroxylase by (R)- warfarin. Chirality 1991;3(1):24-9
45. Yamazaki H, Shimada T. Human liver cytochrome P450 enzymes involved in the 7-hydroxylation of R- and S-warfarin enantiomers. Biochem Pharmacol 1997;54(11):1195-203
46. Draper AJ, Madan A, Parkinson A. Inhibition of coumarin 7-hydroxylase activity in human liver microsomes. Arch Biochem Biophys 1997;341(1):47-61
47. Maenpaa J, Juvonen R, Raunio H, et al. Metabolic interactions of methoxsalen and coumarin in humans and mice. Biochem Pharmacol 1994;48(7):1363-9
48. Takigawa T, Tainaka H, Mihara K, Ogata H. Inhibition of S-warfarin metabolism by nonsteroidal antiinflammatory drugs in human liver microsomes in vitro. Biol Pharm Bull 1998;21(5):541-3
49. Foti RS, Rock DA, Wienkers LC, Wahlstrom JL. Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation. Drug Metab Dispos 2010;38(6):981-7 . Comprehensive analysis of CYP3A4 substrate-dependent inhibition.
50. Ring BJ, Binkley SN, Vandenbranden M, Wrighton SA. In vitro interaction of the antipsychotic agent olanzapine with human cytochromes P450 CYP2C9, CYP2C19, CYP2D6 and CYP3A. Br J Clin Pharmacol 1996;41(3):181-6
51. Isoherranen N, Ludington SR, Givens RC, et al. The influence of CYP3A5 expression on the extent of hepatic CYP3A inhibition is substratedependent: An in vitro-in vivo evaluation. Drug Metab Dispos 2008;36(1):146-54
52. Gibbs MA, Thummel KE, Shen DD, Kunze KL. Inhibition of cytochrome P-450 3A (CYP3A) in human intestinal and liver microsomes: Comparison of Ki values and impact of CYP3A5 expression. Drug Metab Dispos 1999;27(2):180-7
53. von Moltke LL, Greenblatt DJ, Schmider J, et al. Midazolam hydroxylation by human liver microsomes in vitro: Inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents. J Clin Pharmacol 1996b;36(9):783-91
54. 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(2):104-12
55. Jurima-Romet M, Wright M, Neigh S. Terfenadine-antidepressant interactions: An in vitro inhibition study using human liver microsomes. Br J Clin Pharmacol 1998;45(3):318-21
56. Transon C, Leemann T, Dayer P. In vitro comparative inhibition profiles of major human drug metabolising cytochrome P450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1996;50(3):209-15
57. Fischer V, Johanson L, Heitz F, et al. 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 1999;27(3):410-16
58. Andersson TB, Bredberg E, Ericsson H, Sjoberg H. An evaluation of the in vitro metabolism data for predicting the clearance and drug-drug interaction potential of CYP2C9 substrates. Drug Metab Dispos 2004;32(7):715-21
59. Yao C, Kunze KL, Kharasch ED, et al. Fluvoxamine-theophylline interaction: Gap between in vitro and in vivo inhibition constants toward cytochrome P4501A2. Clin Pharmacol Ther 2001;70(5):415-24
60. von Moltke LL, Greenblatt DJ, Duan SX, et al. Phenacetin O-deethylation by human liver microsomes in vitro: Inhibition by chemical probes, SSRI antidepressants, nefazodone and venlafaxine. Psychopharmacol (Berl) 1996;128(4):398-407
61. Bourrie M, Meunier V, Berger Y, Fabre G. Cytochrome P450 isoform inhibitors as a tool for the investigation of metabolic reactions catalyzed by human liver microsomes. J Pharmacol Exp Ther 1996;277(1):321-32
62. Shin JG, Kane K, Flockhart DA. Potent inhibition of CYP2D6 by haloperidol metabolites: Stereoselective inhibition by reduced haloperidol. Br J Clin Pharmacol 2001;51(1):45-52
63. Shin JG, Soukhova N, Flockhart DA. Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro: Preferential inhibition of CYP2D6. Drug Metab Dispos 1999;27(9):1078-84
64. Eagling VA, Back DJ, Barry MG. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol 1997;44(2):190-4
65. 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(3):307-14
66. Wen X, Wang JS, Neuvonen PJ, Backman JT. Isoniazid is a mechanism-based inhibitor of cytochrome P450 1A2, 2A6, 2C19 and 3A4 isoforms in human liver microsomes. Eur J Clin Pharmacol 2002;57(11):799-804
67. Desta Z, Soukhova NV, Flockhart DA. Inhibition of cytochrome P450 (CYP450) isoforms by isoniazid: Potent inhibition of CYP2C19 and CYP3A. Antimicrob Agents Chemother 2001;45(2):382-92
68. Wang JS, Wen X, Backman JT, et al. Midazolam alpha-hydroxylation by human liver microsomes in vitro: Inhibition by calcium channel blockers, itraconazole and ketoconazole. Pharmacol Toxicol 1999;85(4):157-61
69. Emoto C, Murase S, Sawada Y, et al. 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 2003;18(5):287-95
70. McConn DJ, Lin YS, Allen K, et al. Differences in the inhibition of cytochromes P450 3A4 and 3A5 by metabolite-inhibitor complex-forming drugs. Drug Metab Dispos 2004;32(10):1083-91
71. Greenblatt DJ, Zhao Y, Venkatakrishnan K, et al. Mechanism of cytochrome P450-3A inhibition by ketoconazole. J Pharm Pharmacol 2011;63(2):214-21
72. Wandel C, Kim RB, Guengerich FP, Wood AJ. Mibefradil is a P-glycoprotein substrate and a potent inhibitor of both P-glycoprotein and CYP3A in vitro. Drug Metab Dispos 2000;28(8):895-8
73. Fayer JL, Petullo DM, Ring BJ, et al. A novel testosterone 6 beta-hydroxylase activity assay for the study of CYP3A-mediated metabolism, inhibition, and induction in vitro. J Pharmacol Toxicol Methods 2001;46(2):117-23
74. Perloff MD, von Moltke LL, Court MH, et al. Midazolam and triazolam biotransformation in mouse and human liver microsomes: Relative contribution of CYP3A and CYP2C isoforms. J Pharmacol Exp Ther 2000;292(2):618-28
75. Katoh M, Nakajima M, Shimada N, et al. Inhibition of human cytochrome P450 enzymes by 1,4-dihydropyridine calcium antagonists: Prediction of in vivo drug-drug interactions. Eur J Clin Pharmacol 2000;55(11-12):843-52
76. Furuta S, Kamada E, Suzuki T, et al. Inhibition of drug metabolism in human liver microsomes by nizatidine, cimetidine and omeprazole. Xenobiotica 2001;31(1):1-10
77. VandenBranden M, Ring BJ, Binkley SN, Wrighton SA. Interaction of human liver cytochromes P450 in vitro with LY307640, a gastric proton pump inhibitor. Pharmacogenetics 1996;6(1):81-91
78. Wyeth Pharmaceuticals. Pristiq (desvenlafaxine succinate) extended release tablets. NDA#021992; 2008
79. Kobayashi K, Yamamoto T, Chiba K, et al. The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4'-hydroxylase activity in human liver microsomes. Br J Clin Pharmacol 1995;40(5):481-5
80. Back DJ, Tjia JF, Karbwang J, Colbert J. In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulphonamides and quinolines. Br J Clin Pharmacol 1988;26(1):23-9
81. Purba HS, Back DJ, Orme ML. Tolbutamide 4-hydroxylase activity of human liver microsomes: Effect of inhibitors. Br J Clin Pharmacol 1987;24(2):230-4
82. Rehmel JL, Eckstein JA, Farid NA, et al. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos 2006;34(4):600-7
83. Eli Lilly. Effient (prasugrel hydrochloride) tablets. NDA#022307; 2009
84. Lillibridge JH, Liang BH, Kerr BM, et al. Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate. Drug Metab Dispos 1998;26(7):609-16
85. Ring BJ, Binkley SN, Roskos L, Wrighton SA. Effect of fluoxetine, norfluoxetine, sertraline and desmethyl sertraline on human CYP3A catalyzed 1'-hydroxy midazolam formation in vitro. J Pharmacol Exp Ther 1995;275(3):1131-5
86. Goldberg MJ, Ring B, DeSante K, et al. Effect of dirithromycin on human CYP3A in vitro and on pharmacokinetics and pharmacodynamics of terfenadine in vivo. J Clin Pharmacol 1996;36(12):1154-60
87. VandenBrink BM, Isoherranen N. The role of metabolites in predicting drug-drug interactions: Focus on irreversible cytochrome P450 inhibition. Curr Opin Drug Discov Devel 2010;13(1):66-77
88. Ogilvie BW, Yerino P, Kazmi F, et al. The proton pump inhibitor, omeprazole, but not lansoprazole or pantoprazole, is a metabolism-dependent inhibitor of CYP2C19: Implications for coadministration with clopidogrel. Drug Metab Dispos 2011;39(11):2020-33
89. Jones DR, Kim SY, Guderyon M, et al. Hydroxywarfarin metabolites potently inhibit CYP2C9 metabolism of S-warfarin. Chem Res Toxicol 2010;23(5):939-45
90. Yamaori S, Kushihara M, Yamamoto I, Watanabe K. Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes. Biochem Pharmacol 2010;79(11):1691-8
91. Madeira M, Levine M, Chang TK, et al. The effect of cimetidine on dextromethorphan O-demethylase activity of human liver microsomes and recombinant CYP2D6. Drug Metab Dispos 2004;32(4):460-7
92. Higashi E, Nakajima M, Katoh M, et al. Inhibitory effects of neurotransmitters and steroids on human CYP2A6. Drug Metab Dispos 2007;35(4):508-14
93. Nassar AE, King I, Paris BL, et al. An in vitro evaluation of the victim and perpetrator potential of the anticancer agent laromustine (VNP40101M), based on reaction phenotyping and inhibition and induction of cytochrome P450 enzymes. Drug Metab Dispos 2009;37(9):1922-30
94. Forest Laboratories. Bystolic (nebivolol) tablets. NDA#21742; 2009
95. Gilead. Ranexa (ranolazine) tablets. NDA#21526; 2003
96. Ko JW, Desta Z, Soukhova NV, et al. In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: Potent effect on CYP2C19 and CYP2D6. Br j Clin Pharmacol 2000;49(4):343-51
97. Tassaneeyakul W, Birkett DJ, Miners JO. Inhibition of human hepatic cytochrome P4502E1 by azole antifungals, CNS-active drugs and non-steroidal anti-inflammatory agents. Xenobiotica 1998;28(3):293-301
98. Bapiro TE, Egnell AC, Hasler JA, Masimirembwa CM. Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos 2001;29(1):30-5
99. Sauer JM, Long AJ, Ring B, et al. Atomoxetine hydrochloride: Clinical drug-drug interaction prediction and outcome. J Pharmacol Exp Ther 2004;308(2):410-18
100. Nakajima M, Ohyama K, Nakamura S, et al. Inhibitory effects of azelastine and its metabolites on drug oxidation catalyzed by human cytochrome P-450 enzymes. Drug Metab Dispos 1999;27(7):792-7
101. Yamazaki H, Suzuki M, Tane K, et al. In vitro inhibitory effects of troglitazone and its metabolites on drug oxidation activities of human cytochrome P450 enzymes: Comparison with pioglitazone and rosiglitazone. Xenobiotica 2000;30(1):61-70