The biotransformation of prasugrel, a new thienopyridine prodrug, by the human carboxylesterases 1 and 2

Drug Metabolism and Disposition

Volumn 36, Issue 7, 2008, Pages 1227-1232

  Williams, Eric T ^a   Jones, Karen O ^a   Ponsler, G Douglas ^a   Lowery, Shane M ^a   Perkins, Everett J ^a   Wrighton, Steven A ^a   Ruterbories, Kenneth J ^a   Kazui, Miho ^b   Farid, Nagy A ^a  

^a ELI LILLY AND COMPANY   (United States)

^b DAIICHI SANKYO CO   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

2 [1 [2 CYCLOPROPYL 1 (2 FLUOROPHENYL) 2 OXOETHYL] 4 MERCAPTO 3 PIPERIDINYLIDENE]ACETIC ACID; 2 [2 OXO 6,7 DIHYDROTHIENO[3,2 C]PYRIDIN 5 4H) YL] 1 CYCLOPROPYL 2 (2 FLUOROPHENYL)ETHANONE; CARBOXYLESTERASE; CARBOXYLESTERASE 1; CARBOXYLESTERASE 2; CYTOCHROME P450; DRUG METABOLITE; PRASUGREL; PRODRUG; R 138727; R 95913; THIENOPYRIDINE DERIVATIVE; THIOLACTONE;

ARTICLE; BIOTRANSFORMATION; CELL STRAIN CACO 2; CONTROLLED STUDY; DRUG HYDROLYSIS; DRUG METABOLISM; DRUG STRUCTURE; DRUG TRANSPORT; HUMAN; HUMAN CELL; IC 50; MICHAELIS MENTEN KINETICS; PRIORITY JOURNAL; THROMBOCYTE AGGREGATION INHIBITION;

BIOTRANSFORMATION; CACO-2 CELLS; CARBOXYLIC ESTER HYDROLASES; CHROMATOGRAPHY, LIQUID; HUMANS; HYDROLYSIS; PIPERAZINES; PRODRUGS; RECEPTORS, PURINERGIC P2; TANDEM MASS SPECTROMETRY; THIOPHENES;

EID: 46449103184     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.107.020248     Document Type: Article

References (28)

1. Asai F, Jakubowski JA, Naganuma H, Brandt JT, Matsushima N, Hirota T, Freestone S. and Winters KJ (2006) Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopvridine P2Y12 inhibitor: a simile ascending dose study in healthy humans. Platelets 17:209-217.
2. Bencharit S, Morton CL, Xue Y. Potter PM, and Redinbo MR (2003) Structural basis of heroin and cocaine metabolism by a promiscuous human drug-processing enzyme. Nat Struct Biol 10:349-356.
3. Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, Jakuhowski JA, Naganuma H, and Winters KJ (2007) A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 153:66.e9-66.e16.
4. Caplain H, Donat F, Gaud C, and Necciari J (1999) Pharmacokinetics of elopidogrel. Semin Thromb Hemost 25 (Suppl 2):25-28.
5. Copeland RA (1996) Enzymes: A Practical Introduction to Structure, Mechanism, and Data Analysis, Wiley-VCH, New York.
6. Cummins CL, Jacobsen W, Christians U, and Benet LZ (2004) CYP3A4-transfected Caco-2 cells as a tool for understanding biochemical absorption harriers: studies with sirolimus and midazolam. J Pharmacol Exp Ther 308:143-155.
7. Farid NA, McIntosh M, Garofolo F, Wong E, Shwajch A, Kennedy M, Young M, Sarkar P, Kawabata K, Takahashi M, et al. (2007a) Determination of the active and inactive metabolites of prasugrel in human plasma by liquid ehromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 21:169-179.
8. Farid NA, Payne CD, Ernest CS II, Li YG, Winters KJ, Salazar DE, and Small DS (2008) Prasugrel, a new thienopyridine antiplatelet drug, weakly inhibits cytochrome P450 2B6 in humans. J Clin Pharmacol 48:53-59.
9. Farid NA, Smith RL, Gillespie TA, Rash TJ, Blair PE, Kurihara A, and Goldberg MJ (2007b) The disposition of prasugrel, a novel thienopyridine, in humans. Drug Metab Dispos 35:1096-1104.
10. Gachel C (2001) ADP receptors of platelets and their inhibition. Thromb Haemost 86:222-232.
11. Imai T, Imoto M, Sakamoto H, and Hashimoto M (2005) Identification of esterases expressed in Caco-2 cells and effects of their hydrolyzing activity in predicting human intestinal absorption. Drug Metab Dispos 33:1185-1190.
12. Imai T, Taketani M, Shii M. Hosokawa M, and Chiba K (2006) Substrate specificity of carboxylesterase isozymes and their contribution to hydrolase activity in human liver and small intestine. Drug Metab Dispos 34:1734-1741.
13. Kamendulis LM, Brzezinski MR, Pindel EV, Bosron WF, and Dean RA (1996) Metabolism of cocaine and heroin is catalyzed by the same human liver carboxylesterases. J Pharmacol Exp Ther 279:713-717.
14. Kühl PW (1994) Excess-substrate inhibition in enzymology and high-dose inhibition in pharmacology: a reinterprctation. Biochem J 298:171-180.
15. Kurihara A, Hagihara K, Kazui M, Ozeki T, Farid NA, and Ikeda T (2005) In vitro metabolism of antiplatelet agent elopidogrel: cytochrome P450 isoforms responsible for two oxidation steps involved in the active metabolite formation. Drug Metab Rev 37 (Suppl 2):99.
16. Niitsu Y. Jakubowski JA, Sugidachi A, and Asai F (2005) Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity. Semin Thromb Hemost 31:184-194.
17. Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, and Zeldin DC (2006) The human intestinal cytochrome P450 "pie." Drug Metab Dispos 34:880-886.
18. Pindel EV, Kedishvili NY, Abraham TL, Brzezinski MR, Zhang J, Dean RA, and Bosron WF (1997) Purification and cloning of a broad substrate specificity human liver earboxylesterase that catalyzes the hydrolysis of cocaine and heroin. J Biol Chem 272:14769-14775.
19. Rehmel JL, Eckstein JA, Farid NA, Heim JB, Kasper SC, Kurihara A, Wrighton SA, and Ring BJ (2006) Interactions of two major metabolites of prasugrel, a thienopyridine anliplatelet agent, with the cytochromes P450. Drag Metab Dispos 34:600-607.
20. Sanghani SP, Quinney SK, Fredenburg TB, Davis WI, Murry DJ, and Bosron WF (2004) Hydrolysis of irinotcean and its oxidative metabolites, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxyeamplothecin, by human carboxylesterases CES1A1, CES2, and a newly expressed carboxylesterase isoenzyme, CES3. Drug Metab Dispos 32:505-511.
21. Satoh T and Hosokawa M (1998) The mammalian carboxylesterases: from molecules to functions. Annu Rev Pharmacol Toxicol 38:257-288.
22. Satoh T, Taylor P, Bosron WF, Sanghani SP, Hosokawa M, and La Du BN (2002) Current progress on esterases: from molecular structure to function. Drug Metab Dispos 30:488-493.
23. Sugidachi A, Ogawa T, Kurihara A, Hagihara K, Jakubowski JA, Hashimoto M, Niitsu Y, and Asai F (2007) The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelei activity to that of clopidogrel's active metabolite. J Thromb Haemost 5:1545-1551.
24. Taketani M, Shii M, Ohura K, Ninomiya S, and Imai T (2007) Carboxylesterase in the liver and small intestine of experimental animals and human. Life Sci 81:924-932.
25. Tang M, Mukundan M, Yang J, Charpentier N, LeCluyse EL, Black C, Yang D, Shi D, and Yan B (2006) Antiplatelet agents aspirin and clopidogrel are hydrolyzed by distinct carboxylesterases, and clopidogrel is transesterificated in the presence of ethyl alcohol. J Pharmacol Exp Ther 319:1467-1476.
26. Wadkins RM, Morton CL, Weeks JK, Oliver L, Wierdl M, Danks MK, and Potter PM (2001) Structural constraints affect the metabolism of 7-elhyl-10-[4-(1- pipcridino)-1-pipcridino]car-bonyloxycamptothecin (CPT-11) by carboxylesterases. Mol Pharmacol 60:355-362.
27. Williams ET, Ehsani ME, Wang X, Wang H, Qian YW, Wrighton SA, and Perkins EJ (2008) Effect of buffer components and carrier solvents on in vitro activity of recombinant human carboxylesterases. J Pharmacol Toxicol Methods 57:138-144.
28. Williams JA, Ring BJ, Cantrell VE, Jones DR, Eckstein J, Ruterbories K, Hamman MA, Hall SD, and Wrighton SA (2002) Comparative metabolic capabilities of CYP3A4, CYP3A5, and CYP3A7. Drug Metab Dispos 30:883-891.