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Research Article

Mechanism-based inactivation of human cytochrome P450 enzymes: strategies for diagnosis and drug–drug interaction risk assessment

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Pages 1225-1256 | Received 11 Jul 2007, Accepted 08 Sep 2007, Published online: 22 Sep 2008

References

  • Austin RP, Barton P, Cockroft SL, Wenlock MC, Riley RJ. The influence of non-specific microsomal binding on apparent intrinsic clearance, and its prediction from physicochemical properties. Drug Metabolism and Disposition 2002; 30(12)1497–1503
  • Awni WM, Braeckman RA, Granneman GR, Witt G, Dube LM. Pharmacokinetics and pharmacodynamics of zileuton after oral administration of single and multiple dose regimens of zileuton 600 mg in healthy volunteers. Clinical Pharmacokinetics 1995; 29(Suppl. 2)22–33
  • Bertelsen KM, Venkatakrishnan K, Von Moltke LL, Obach RS, Greenblatt DJ. Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: Comparison with fluoxetine and quinidine. Drug Metabolism and Disposition 2003; 31(3)289–293
  • Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J, King SP, Miwa G, Ni L, et al. The conduct of in vitro and in vivo drug–drug interaction studies: A Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metabolism and Disposition 2003; 31(7)815–832
  • Busse D, Cosme J, Beaune P, Kroemer HK, Eichelbaum M. Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans. Naunyn Schmiedebergs Archives in Pharmacology 1995; 353(1)116–121
  • Christensen H, Baker M, Tucker GT, Rostami-Hodjegan A. Prediction of plasma protein binding displacement and its implications for quantitative assessment of metabolic drug–drug interactions from in vitro data. Journal of Pharmaceutical Science 2006; 95(12)2778–2787
  • Cloyd J, Marino S, Brundage R, Birnbaum AK, Ramsay RE, Pennell P, Rarick JO, Mishra U, White JR, Leppik IE. Time course of enzyme de-induction of carbamazepine metabolism. Clinical Pharmacology and Therapeutics 2007; 81(Suppl. 1)S46–S47
  • Correia MA. Cytochrome P450 turnover. Methods in Enzymology 1991; 206: 315–325
  • Correia MA, Ortiz de Montellano PR. Cytochrome P450. Structure, mechanism, and biochemistry. Inhibition of cytochrome P450 enzymes, PR Ortiz de Montellano. Kluwer/Plenum, New York, NY 2005; 247–322
  • Emery MG, Jubert C, Thummel KE, Kharasch ED. Duration of cytochrome P-450 2E1 (CYP2E1) inhibition and estimation of functional CYP2E1 enzyme half-life after single-dose disulfiram administration in humans. Journal of Pharmacology and Experimental Therapy 1999; 291(1)213–239
  • Ernest CS, II, Hall SD, Jones DR. Mechanism-based inactivation of cytochrome P4503A (CYP3A) by HIV Protease Inhibitors. Journal of Pharmacology and Experimental Therapeutics 2005; 312(2)583–591
  • Faber MS, Fuhr U. Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clinical Pharmacology and Therapy 2004; 76(2)178–184
  • Franklin MR. The enzymatic formation of a methylene dioxyphenyl derivative exhibiting an isocyanide-like spectrum with reduced cytochrome P-450 in hepatic microsomes. Xenobiotica 1971; 1: 581–591
  • Fromm MF, Busse D, Kroemer HK, Eichelbaum M. Differential induction of prehepatic and hepatic metabolism of verapamil by rifampin. Hepatology 1996; 24(4)796–801
  • Galetin A, Burt H, Gibbons L, Houston JB. Prediction of time-dependent CYP3A4 drug–drug interactions: Impact of enzyme degradation, parallel elimination pathways, and intestinal inhibition. Drug Metabolism and Disposition 2006; 34(1)166–175
  • Ghanbari F, Rowland-Yeo K, Bloomer JC, Clarke SE, Lennard MS, Tucker GT, Rostami-Hodjegan A. A critical evaluation of the experimental design of studies of mechanism based enzyme inhibition, with implications for in vitro–in vivo extrapolation. Current Drug Metabolism 2006; 7(3)315–334
  • Granneman GR, Braeckman RA, Locke CS, Cavanaugh JH, Dube LM, Awni WM. Effect of zileuton on theophylline pharmacokinetics. Clinical Pharmacokinetics 1995; 29(Suppl. 2)77–83
  • Greenblatt DJ, Von Moltke LL, Harmatz JS, Chen G, Weemhoff JL, Jen C, Kelley CJ, LeDuc BW, Zinny MA. Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice. Clinical Pharmacology and Therapy 2003; 74(2)121–129
  • Hallifax D, Houston JB. Binding of drugs to hepatic microsomes: Comment and assessment of current prediction methodology with recommendation for improvement. Drug Metabolism and Disposition 2006; 34(4)724–726
  • Hemeryck A, De Vriendt CA, Belpaire FM. Metoprolol–paroxetine interaction in human liver microsomes: Stereoselective aspects and prediction of the in vivo interaction. Drug Metabolism and Disposition 2001; 29(5)656–663
  • Hsu A, Granneman GR, Witt G, Locke C, Denissen J, Molla A, Valdes J, Smith J, Erdman K, Lyons N, et al. Multiple-dose pharmacokinetics of ritonavir in human immunodeficiency virus-infected subjects. Antimicrobial Agents and Chemotherapy 1997; 41(5)898–905
  • 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 Metabolism and Disposition 2005; 33(6)837–844
  • Jones HM, Houston JB. Substrate depletion approach for determining in vitro metabolic clearance: Time dependencies in hepatocyte and microsomal incubations. Drug Metabolism and Disposition 2004; 32: 973–982
  • Kalgutkar AS, Obach RS, Maurer TS. Mechanism-based inactivation of cytochrome p450 enzymes: Chemical mechanisms, structure–activity relationships and relationship to clinical drug–drug interactions and idiosyncratic adverse drug reactions. Current Drug Metabolism 2007; 8(5)407–447
  • Kanamitsu S, Ito K, Green CE, Tyson CA, Shimada N, Sugiyama Y. Prediction of in vivo interaction between triazolam and erythromycin based on in vitro studies using human liver microsomes and recombinant human CYP3A4. Pharmacology Research 2000; 17(4)419–426
  • Karjalainen MJ, Neuvonen PJ, Backman JT. Rofecoxib is a potent, metabolism-dependent inhibitor of CYP1A2: implications for in vitro prediction of drug interactions. Drug Metabolism and Disposition 2006; 34(12)2091–2096
  • Kharasch ED, Hoffer C, Whittington D, Sheffels P. Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone. Clinical Pharmacology and Therapy 2004; 76(3)250–269
  • Kumar GN, Rodrigues AD, Buko AM, Denissen JF. Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. Journal of Pharmacology and Experimental Therapy 1996; 277(1)423–431
  • Lin JH. CYP induction-mediated drug interactions: In vitro assessment and clinical implications. Pharmacology Research 2006; 23(6)1089–1116
  • Liston HL, DeVane CL, Boulton DW, Risch SC, Markowitz JS, Goldman J. Differential time course of cytochrome P450 2D6 enzyme inhibition by fluoxetine, sertraline, and paroxetine in healthy volunteers. Journal of Clinical Psychopharmacology 2002; 22(2)169–173
  • Lu P, Schrag ML, Slaughter DE, Raab CE, Shou M, Rodrigues AD. Mechanism-based inhibition of human liver microsomal cytochrome P450 1A2 by zileuton, a 5-lipoxygenase inhibitor. Drug Metabolism and Disposition 2003; 31(11)1352–1360
  • Lucas D, Menez C, Girre C, Bodenez P, Hispard E, Menez JF. Decrease in cytochrome P4502E1 as assessed by the rate of chlorzoxazone hydroxylation in alcoholics during the withdrawal phase. Alcohol: Clinical and Experimental Research 1995; 19(2)362–366
  • Margolis JM, Obach RS. Impact of non-specific binding to microsomes and phospholipid on the inhibition of cytochrome P4502D6: Implications for relating in vitro inhibition data to in vivo drug interactions. Drug Metabolism and Disposition 2003; 31(5)606–611
  • Mayhew BS, Jones DR, Hall SD. An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation. Drug Metabolism and Disposition 2000; 28(9)1031–1037
  • Monks TJ, Caldwell J, Smith RL. Influence of methylxanthine-containing foods on theophylline metabolism and kinetics. Clinical Pharmacology and Therapy 1979; 26(4)513–524
  • Obach RS. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and non-specific binding to microsomes. Drug Metabolism and Disposition 1999; 27(11)1350–1359
  • Obach RS. Drug–drug interactions: An important negative attribute in drugs. Drugs Today (Barcelona) 2003; 39(5)301–338
  • Obach RS, Reed-Hagen AE. Measurement of Michaelis constants for cytochrome P450-mediated biotransformation reactions using a substrate depletion approach. Drug Metabolism and Disposition 2002; 30: 831–837
  • Obach RS, Walsky RL, Venkatakrishnan K, Gaman EA, Houston JB, Tremaine LM. The utility of in vitro cytochrome P450 inhibition data in the prediction of drug–drug interactions. Journal of Pharmacology and Experimental Therapy 2006; 316(1)336–348
  • Obach RS, Walsky RL, Venkatakrishnan K, Houston JB, Tremaine LM. In vitro cytochrome P450 inhibition data and the prediction of drug–drug interactions: Qualitative relationships, quantitative predictions, and the rank-order approach. Clinical Pharmacology and Therapy 2005; 78(6)582–592
  • Obach RS, Walsky RL, Venkatakrishnan K. Mechanism based inactivation of human cytochrome P450 enzymes and the prediction of drug–drug interactions. Drug Metabolism and Disposition 2007; 35(2)246–255
  • Ortiz de Montellano PR, Kunze KL. Shift of the acetylenic hydrogen during chemical and enzymatic oxidation of the biphenylacetylene triple bond. Archives in Biochemistry and Biophysics 1981; 209(2)710–712
  • Ortiz de Montellano PR, Mathews JM. Autocatalytic alkylation of the cytochrome P-450 prosthetic haem group by 1-aminobenzotriazole. Isolation of an NN-bridged benzyne-protoporphyrin IX adduct. Biochemistry Journal 1981; 195(3)761–764
  • Pelkonen O, Myllynen P, Taavitsainen P, Boobis AR, Watts P, Lake BG, Price RJ, Renwick AB, Gomez-Lechon MJ, Castell JV, et al. Carbamazepine: A ‘blind’ assessment of CVP-associated metabolism and interactions in human liver-derived in vitro systems. Xenobiotica 2001; 31(6)321–343
  • Pichard L, Fabre I, Daujat M, Domergue J, Joyeux H, Maurel P. Effect of corticosteroids on the expression of cytochromes P450 and on cyclosporin A oxidase activity in primary cultures of human hepatocytes. Molecular Pharmacology 1992; 41(6)1047–1055
  • Renwick AB, Watts PS, Edwards RJ, Barton PT, Guyonnet I, Price RJ, Tredger JM, Pelkonen O, Boobis AR, Lake BG. Differential maintenance of cytochrome P450 enzymes in cultured precision-cut human liver slices. Drug Metabolism and Disposition 2000; 28(10)1202–1209
  • Riley RJ, Grime K, Weaver R. Time-dependent CYP inhibition. Expert Opinions on Drug Metabolism and Toxicology 2007; 3(1)51–66
  • Roberts BJ, Song BJ, Soh Y, Park SS, Shoaf SE. Ethanol induces CYP2E1 by protein stabilization. Role of ubiquitin conjugation in the rapid degradation of CYP2E1. Journal of Biology and Chemistry 1995; 270(50)29632–29635
  • Rostami-Hodjegan A, Tucker G. ‘In silico’ simulations to assess the ‘in vivo’ consequences of ‘in vitro’ metabolic drug–drug interactions. Drug Discovery Today: Technologies 2004; 1(4)441–448
  • Rostami-Hodjegan A, Tucker GT. Simulation and prediction of in vivo drug metabolism in human populations from in vitro data. Nature Reviews in Drug Discovery 2007; 6(2)140–148
  • Rostami-Hodjegan A, Wolff K, Hay AW, Raistrick D, Calvert R, Tucker GT. Population pharmacokinetics of methadone in opiate users: characterization of time-dependent changes. British Journal of Clinical Pharmacology 1999; 48(1)43–52
  • Shen DD, Kunze KL, Thummel KE. Enzyme-catalysed processes of first-pass hepatic and intestinal drug extraction. Advances in Drug Delivery Reviews 1997; 27(2–3)99–127
  • Silverman RB. Mechanism-base enzyme inactivation. Chemistry and enzymology. CRC Press, Boca Raton, FL 1998
  • Soars MG, McGinnity DF, Grime K, Riley RJ. The pivotal role of hepatocytes in drug discovery. Chemico-Biology Interactions 2007; 168(1)2–15
  • Sun D, Lennernas H, Welage LS, Barnett JL, Landowski CP, Foster D, Fleisher D, Lee KD, Amidon GL. Comparison of human duodenum and Caco-2 gene expression profiles for 12,000 gene sequences tags and correlation with permeability of 26 drugs. Pharmacology Research 2002; 19(10)1400–1416
  • Sweeny DJ, Nellans HN. Stereoselective glucuronidation of zileuton isomers by human hepatic microsomes. Drug Metabolism and Disposition 1995; 23(1)149–153
  • Thummel KE, Kunze KL, Shen DD. Metabolically based drug–drug interactions: principles and mechanisms. Metabolic drug interactions, RH Levy, KE Thummel, WF Trager, PG Hansten, M Eichelbaum. Lippincott Williams & Wilkins, Philadelphia, PA 2000; 3–19
  • Tucker GT, Houston JB, Huang SM. Optimizing drug development: strategies to assess drug metabolism/transporter interaction potential — towards a consensus. British Journal of Clinical Pharmacology 2001; 52(1)107–117
  • US Food and Drug Administration (USFDA). (2006) (available at: ) (accessed on 17 November 2006)
  • Van LM, Hargreaves JA, Lennard MS, Tucker GT, Rostami-Hodjegan A. Inactivation of CYP2D6 by methylenedioxymethamphetamine in different recombinant expression systems. European Journal of Pharmaceutical Science 2007a; 32(1)8–16
  • Van LM, Heydari A, Yang J, Hargreaves J, Rowland-Yeo K, Lennard MS, Tucker GT, Rostami-Hodjegan A. The impact of experimental design on assessing mechanism-based inactivation of CYP2D6 by MDMA (Ecstasy). Journal of Psychopharmacology 2006; 20: 834–841
  • Van LM, Swales J, Hammond C, Wilson C, Hargreaves JA, Rostami-Hodjegan A. Kinetics of the time-dependent inactivation of CYP2D6 in cryopreserved human hepatocytes by methylenedioxymethamphetamine (MDMA). European Journal of Pharmaceutical Science 2007b; 31(1)53–61
  • Venkatakrishnan K, Obach RS. In vitro–in vivo extrapolation of CYP2D6 inactivation by paroxetine: Prediction of nonstationary pharmacokinetics and drug interaction magnitude. Drug Metabolism and Disposition 2005; 33(6)845–852
  • Venkatakrishnan K, Obach RS. Drug–drug interactions via mechanism-based cytochrome P450 inactivation: Points to consider for risk assessment from in vitro data and clinical pharmacologic evaluation. Current Drug Metabolism 2007; 8(5)449–462
  • Venkatakrishnan K, Von Moltke LL, Obach RS, Greenblatt DJ. Drug metabolism and drug interactions: Application and clinical value of in vitro models. Current Drug Metabolism 2003; 4(5)423–459
  • Walsky RL, Obach RS. Validated assays for human cytochrome P450 activities. Drug Metabolism and Disposition 2004; 32(6)647–660
  • Wang YH, Jones DR, Hall SD. Prediction of cytochrome P450 3A inhibition by verapamil enantiomers and their metabolites. Drug Metabolism and Disposition 2004; 32(2)259–266
  • Watkins PB, Wrighton SA, Schuetz EG, Maurel P, Guzelian PS. Macrolide antibiotics inhibit the degradation of the glucocorticoid-responsive cytochrome P-450p in rat hepatocytes in vivo and in primary monolayer culture. Journal of Biology and Chemistry 1986; 261(14)6264–6271
  • Wilkinson GR. Drug metabolism and variability among patients in drug response. New England Journal of Medicine 2005; 352(21)2211–2221
  • Wu CY, Benet LZ. Predicting drug disposition via application of BCS: Transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharmacology Research 2005; 22(1)11–23
  • Yang J, Jamei M, Heydari A, Yeo K, De La Torre R, Farre M, Tucker GT, Rostami-Hodjegan A. Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA. Journal of Psychopharmacology 2006; 20(6)842–849
  • Yang J, Jamei M, Yeo KR, Tucker GT, Rostami-Hodjegan A. Kinetic values for mechanism-based enzyme inhibition: Assessing the bias introduced by the conventional experimental protocology. European Journal of Pharmaceutical Science 2005; 25(3–4)334–340
  • Yang J, Jamei M, Yeo KR, Tucker GT, Rostami-Hodjegan A. Theoretical assessment of a new experimental protocology for determining kinetic values describing mechanism (time)-based enzyme inhibition. European Journal of Pharmaceutical Science 2007a; 31: 232–241
  • Yang J, Jamei M, Yeo KR, Tucker GT, Rostami-Hodjegan A. Prediction of intestinal first-pass drug metabolism. Current Drug Metabolism 2007b, (in press)
  • Yang J, Kjellsson M, Rostami-Hodjegan A, Tucker GT. The effects of dose staggering on metabolic drug–drug interactions. European Journal of Pharmaceutical Science 2003; 20(2)223–232

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