Potent Mechanism-Based Inhibition of Human CYP2B6 by Clopidogrel and Ticlopidine

Journal of Pharmacology and Experimental Therapeutics

Volumn 308, Issue 1, 2004, Pages 189-197

  Richter, Tanja ^a   Mürdter, Thomas E ^a   Heinkele, Georg ^a   Pleiss, Jürgen ^b   Tatzel, Stephan ^b   Schwab, Matthias ^a   Eichelbaum, Michel ^a   Zanger, Ulrich M ^a  

^a DR MARGARETE FISCHER BOSCH INSTITUTE OF CLINICAL PHARMACOLOGY   (Germany)

^b UNIVERSITY OF STUTTGART   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

7 ETHOXYCOUMARIN; ADENOSINE DIPHOSPHATE; AMFEBUTAMONE; CLOPIDOGREL; COUMARIN; CYTOCHROME P450 1A2; CYTOCHROME P450 2B6; CYTOCHROME P450 2C19; DIETHYLDITHIOCARBAMIC ACID; FURAFYLLINE; HEMOPROTEIN; KETOCONAZOLE; MEPHENYTOIN; PRODRUG; PROPAFENONE; PYRIDINE DERIVATIVE; QUINIDINE; RECOMBINANT ENZYME; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; SULFAPHENAZOLE; THIOTEPA; TICLOPIDINE; UNSPECIFIC MONOOXYGENASE; VERAPAMIL;

ARTICLE; CONCENTRATION RESPONSE; DEMETHYLATION; DOSE TIME EFFECT RELATION; DRUG HYDROXYLATION; DRUG INACTIVATION; DRUG MECHANISM; DRUG METABOLISM; DRUG OXIDATION; DRUG POTENCY; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME STRUCTURE; ENZYME SUBSTRATE; HUMAN; LIVER MICROSOME; MODEL; PRIORITY JOURNAL; THROMBOCYTE AGGREGATION INHIBITION;

ARYL HYDROCARBON HYDROXYLASES; BUPROPION; CYTOCHROME P-450 ENZYME SYSTEM; HUMANS; HYDROXYLATION; KINETICS; MICROSOMES, LIVER; OXIDOREDUCTASES, N-DEMETHYLATING; PLATELET AGGREGATION INHIBITORS; TICLOPIDINE;

EID: 0346497703     PISSN: 00223565     EISSN: None     Source Type: Journal    
DOI: 10.1124/jpet.103.056127     Document Type: Article

References (40)

1. Bathelt C, Schmid RD, and Pleiss J (2002) Regioselectivity of CYP2B6: homology modeling, molecular dynamics simulation, docking. J Mol Model 8:327-335.
2. Beaune P, Dansette PM, Mansuy D, Kiffel L, Finck M, Amar C, Leroux JP, and Homberg JC (1987) Human anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug. Proc Natl Acad Sci USA 84:551-555.
3. Clarke TA and Waskell LA (2002) The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin. Drug Metab Dispos 31:53-59.
4. Court MH, Duan SX, Hesse LM, Venkatakrishnan K, and Greenblatt DJ (2001) Cytochrome P-450 2B6 is responsible for interindividual variability of propofol hydroxylation by human liver microsomes. Anesthesiology (Hagerst) 94:110-119.
5. Ding Z, Kim S, Dorsam RT, Jin J, and Kunapuli SP (2003) Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270. Blood 101:3908-3914.
6. Donahue SR, Flockhart DA, Abernethy DR, and Ko JW (1997) Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19. Clin Pharmacol Ther 62:572-577.
7. Ekins S and Wrighton SA (1999) The role of CYP2B6 in human xenobiotic metabolism. Drug Metab Rev 31:719-754.
8. Faucette SR, Hawke RL, Lecluyse EL, Shord SS, Yan B, Laethem RM, and Lindley CM (2000) Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos 28:1222-1230.
9. Gervot L, Rochat B, Gautier JC, Bohnenstengel F, Kroemer H, de Berardinis V, Martin H, Beaune P, and de Waziers I (1999) Human CYP2B6: expression, inducibility and catalytic activities. Pharmacogenetics 9:295-306.
10. Granvil CP, Madan A, Sharkawi M, Parkinson A, and Wainer IW (1999) Role of CYP2B6 and CYP3A4 in the in vitro N-dechloroethylation of (R)- and (S)-ifosfamide in human liver microsomes. Drug Metab Dispos 27:533-541.
11. Ha-Duong NT, Dijols S, Macherey AC, Goldstein JA, Dansette PM, and Mansuy D (2001) Ticlopidine as a selective mechanism-based inhibitor of cytochrome P4502C19. Biochemistry 40:12112-12122.
12. Hesse L, Venkatakrishnan K, Court M, von Moltke L, Duan X, Shader RI, and Greenblatt DJ (2000) CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos 28:1176-1183.
13. Hesse LM, von Moltke LL, Shader RI, and Greenblatt DJ (2001) Ritonavir, efavirenz and nelfinavir inhibit CYP2B6 activity in vitro: potential drug interactions with bupropion. Drug Metab Dispos 29:100-102.
14. Hidestrand M, Osxarson M, Salamen JS, Nyman L, Pelkonen O, Turpeinen M, and Ingelman-Sundberg M (2001) CYP2B6 and CYP2C19 as the major enzymes responsible for the metabolism of selegiline, a drug used in the treatment of Parkinson's disease, as revealed from experiments with recombinant enzymes. Drug Metab Dispos 29:1480-1484.
15. Hofmann U, Pecia M, Heinkele G, Dilger K, Kroemer HK, and Eichelbaum M (2000) Determination of propafenone and its phase I and phase II metabolites in plasma and urine by high-performance liquid chromatography-electrospray ionization mass spectrometry. J Chromatogr B Biomed Sci Appl 748:113-123.
16. Huitema AD, Kerbusch T, Tibben MM, Rodenhuis S, and Beijnen JH (2000) Reduction of cyclophosphamide bioactivation by thioTEPA: critical sequence-dependency in high-dose chemotherapy regimens. Cancer Chemother Pharmacol 46:119-127.
17. Jushchyshyn MI, Kent UM, and Hollenberg PF (2002) The mechanism-based inactivation of human cytochrome P450 2B6 by phencyclidine. Drug Metab Dispos 31:46-52.
18. Kam PC and Nethery CM (2003) The thienopyridine derivates (platelet adenosine diphosphate receptor antagonists), pharmacology and clinical development. Anaesthesia 58:28-35.
19. Kent UM, Mills DE, Rajnarayanan RV, Alworth WL, and Hollenberg PF (2001) Effect of 17-alpha-ethynylestradiol on activities of cytochrome P450 2B (P450 2B) enzymes: characterization of inactivation of P450s 2B1 and 2B6 and identification of metabolites. J Pharmacol Exp Ther 300:549-558.
20. Lang T, Klein K, Fischer J, Nüssler AK, Neuhaus P, Hofmann U, Eichelbaum M, Schwab M, and Zanger UM (2001) Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 11:399-415.
21. Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, and Bates ER (2003) Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 107:32-37.
22. Lopez-Garcia MP, Dansette PM, and Mansuy D (1994) Thiophene derivatives as new mechanism-based inhibitors of cytochromes P450: inactivation of yeast-expressed human liver cytochrome P450 2C9 by tienilic acid. Biochemistry 33:166-175.
23. Mehta NB and Raleigh NC (1974), inventors; Burroughs Wellcome (now GlasxoSmithKline), assignee. Meta chloro substituted-α -butylaminopropiophenones. U.S. patent 3,819,706. 1974 June 25.
24. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK, Malmberg K, Rupprecht H, Zhao F, Chrolavicius S, et al. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators (2001) Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 358:527-533.
25. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, and Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639-1662.
26. Pereillo JM, Maftouh M, Andrieu A, Uzabiaga MF, Fedeli O, Savi P, Pascal M, Herbert JM, Maffrand JP, and Picard C (2002) Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Dispos 30:1288-1295.
27. Rae JM, Soukhova NV, Flockhart DA, and Desta Z (2002) Triethylenethiophosphoramide is a specific inhibitor of cytochrome P450 2B6: implications for cyclophosphamide metabolism. Drug Metab Dispos 30:525-530.
28. Roy P, Yu LJ, Crespi CL, and Waxman DJ (1999) Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos 27:654-666.
29. Savi P, Combalbert J, Gaich C, Rouchon MC, Maffrand JP, Berger Y, and Herbert JM (1994) The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-1A. Thromb Haemostasis 72:313-317.
30. Savi P, Herbert JM, Pflieger AM, Dol F, Delebassee D, Combalbert J, Defreyn G, Maffrand JP (1992) Importance of hepatic metabolism in the antiaggregating activity of the thienopyridine clopidogrel. Biochem Pharmacol 44:527-532.
31. Savi P, Pereillo JM, Uzabiaga MF, Combalbert J, Picard C, Maffrand JP, Pascal M, and Herbert JM (2000) Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemostasis 84:891-896.
32. Silverman RB (1995) Mechanism-based enzyme inactivators. Methods Enzymol 249:240-283.
33. Stiborova M, Borek-Dohalska L, Hodek P, Mraz J, and Frei E (2002) New selective inhibitors of cytochromes P450 2B and their application to antimutagenesis of tamoxifen. Arch Biochem Biophys 403:41-49.
34. Tateishi T, Kumai T, Watanabe M, Nakura H, Tanaka M, and Kobayashi S (1999) Ticlopidine decreased the in vivo activity of CYP2C19 as measured by omeprazole metabolism. Br J Clin Pharmacol 47:454-457.
35. 7]verapamil and metabolites in biological fluids by liquid chromatography-mass spectrometry. J Chromatogr B Biomed Sci Appl 738:137-147.
36. Ward BA, Gorski JC, Jones DR, Hall SD, Flockhart DA, and 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 306:287-300.
37. Yamazaki H, Inoue K, Hashimoto M, and Shimada T (1999a) Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Arch Toxicol 73:65-70.
38. Yamazaki H, Tanaka M, and Shimada T (1999b) Highly sensitive high-performance liquid chromatographic assay for coumarin 7-hydroxylation and 7-ethoxycoumarin O-deethylation by human liver cytochrome P450 enzymes. J Chromatogr B Biomed Sci Appl 721:13-19.
39. Yanagihara Y, Kariya S, Ohtani M, Uchino K, Aoyama T, Yamamura Y, and Iga T (2001) Involvement of CYP2B6 in n-demethylation of ketamine in human liver microsomes. Drug Metab Dispos 29:887-890.
40. Yanev S, Kent UM, Pandova B, and Hollenberg PF (1999) Selective mechanism-based inactivation of cytochromes P-450 2B1 and P-450 2B6 by a series of xanthates. Drug Metab Dispos 27:600-604.