![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Department of Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.L.F.R., J.A.E., N.A.F., J.B.H., S.C.K., S.A.W., and B.J.R.); and Drug Metabolism and Pharmacokinetics Research Labs., Sankyo Co., Ltd., Tokyo, Japan (A.K.)
The biotransformation of prasugrel to R-138727 (2-[1-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid) involves rapid deesterification to R-95913 (2-[2-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone) followed by cytochrome P450 (P450)-mediated formation of R-138727, the metabolite responsible for platelet aggregation. For identification of the P450s responsible for the formation of the active metabolite, the current studies were conducted with R-95913 as the substrate. Incubations required supplementation with reduced glutathione. Hyperbolic kinetics (Km 21–30 µM), consistent with a single enzyme predominating, were observed after incubations with human liver microsomes. Correlation analyses revealed a strong relationship between R-138727 formation and CYP3A-mediated midazolam 1'-hydroxylation (r2 = 0.98; p < 0.001) in a bank of characterized human liver microsomal samples. The human lymphoblast-expressed enzymes capable of forming R-138727, in rank order of rates, were CYP3A4>CYP2B6>CYP2C19
CYP2C9>CYP2D6. A monoclonal antibody to CYP2B6 and the CYP3A inhibitor ketoconazole substantially inhibited R-138727 formation, whereas inhibitors of CYP2C9 (sulfaphenazole) and CYP2C19 (omeprazole) did not. Scaling of in vitro intrinsic clearance values from expressed enzymes to the whole liver using a relative abundance approach indicated that either CYP3A4 alone or CYP3A4 and CYP2B6 are the major contributors to R-138727 formation. R-95913 and R-138727 were also examined for their ability to inhibit metabolism mediated by five P450s. R-138727 did not inhibit the P450s tested. In vitro, R-95913 inhibited CYP2C9, CYP2C19, CYP2D6, and CYP3A, with Ki values ranging from 7.2 µM to 82 µM, but did not inhibit CYP1A2. These Ki values exceed circulating concentrations in humans by 3.8- to 43-fold. Therefore, neither R-95913 nor R-138727 is expected to substantially inhibit the P450-mediated metabolism of coadministered drugs.
This article has been cited by other articles:
|
|
 |
|
  K. Hagihara, M. Kazui, A. Kurihara, M. Yoshiike, K. Honda, O. Okazaki, N. A. Farid, and T. Ikeda A Possible Mechanism for the Differences in Efficiency and Variability of Active Metabolite Formation from Thienopyridine Antiplatelet Agents, Prasugrel and Clopidogrel Drug Metab. Dispos., November 1, 2009; 37(11): 2145 - 2152. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Wallentin P2Y12 inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use Eur. Heart J., August 2, 2009; 30(16): 1964 - 1977. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Verstuyft, T. Simon, and R. B. Kim Personalized medicine and antiplatelet therapy: ready for prime time? Eur. Heart J., August 2, 2009; 30(16): 1943 - 1963. [Full Text] [PDF]
|
|
|
|
 |
|
 C. S. Ernest II, M. A. Heathman, and R. E. Wrishko Prediction of Prasugrel Active Metabolite Concentrations From 2 Downstream Inactive Metabolite Concentrations Using Multilinear Regression Analysis J. Clin. Pharmacol., August 1, 2009; 49(8): 973 - 983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. E. Wrishko, C. S. Ernest II, D. S. Small, Y. G. Li, G. J. Weerakkody, J. R. Riesmeyer, W. L. Macias, S. Rohatagi, D. E. Salazar, E. M. Antman, et al. Population Pharmacokinetic Analyses to Evaluate the Influence of Intrinsic and Extrinsic Factors on Exposure of Prasugrel Active Metabolite in TRITON-TIMI 38 J. Clin. Pharmacol., August 1, 2009; 49(8): 984 - 998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Varenhorst, S. James, D. Erlinge, J. T. Brandt, O. O. Braun, M. Man, A. Siegbahn, J. Walker, L. Wallentin, K. J. Winters, et al. Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease Eur. Heart J., July 2, 2009; 30(14): 1744 - 1752. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Mega, S. L. Close, S. D. Wiviott, L. Shen, R. D. Hockett, J. T. Brandt, J. R. Walker, E. M. Antman, W. L. Macias, E. Braunwald, et al. Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel: Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes Circulation, May 19, 2009; 119(19): 2553 - 2560. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Veverka and J. M. Hammer Prasugrel: A New Thienopyridine Inhibitor Journal of Pharmacy Practice, April 1, 2009; 22(2): 158 - 165. [Abstract] [PDF]
|
|
|
|
|
|
Y. Nishiya, K. Hagihara, T. Ito, M. Tajima, S.-i. Miura, A. Kurihara, N. A. Farid, and T. Ikeda Mechanism-Based Inhibition of Human Cytochrome P450 2B6 by Ticlopidine, Clopidogrel, and the Thiolactone Metabolite of Prasugrel Drug Metab. Dispos., March 1, 2009; 37(3): 589 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Mega, S. L. Close, S. D. Wiviott, L. Shen, R. D. Hockett, J. T. Brandt, J. R. Walker, E. M. Antman, W. Macias, E. Braunwald, et al. Cytochrome P-450 Polymorphisms and Response to Clopidogrel N. Engl. J. Med., January 22, 2009; 360(4): 354 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Scott, R. M Norwood, and D. Parra P2Y12 Inhibitors in Cardiovascular Disease: Focus on Prasugrel Ann. Pharmacother., January 1, 2009; 43(1): 64 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. T. Williams, K. O. Jones, G. D. Ponsler, S. M. Lowery, E. J. Perkins, S. A. Wrighton, K. J. Ruterbories, M. Kazui, and N. A. Farid The Biotransformation of Prasugrel, a New Thienopyridine Prodrug, by the Human Carboxylesterases 1 and 2 Drug Metab. Dispos., July 1, 2008; 36(7): 1227 - 1232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. Riley, M. J. Tafreshi, and S. L. Haber Prasugrel: A novel antiplatelet agent Am. J. Health Syst. Pharm., June 1, 2008; 65(11): 1019 - 1028. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Trenk, W. Hochholzer, M. F. Fromm, L.-E. Chialda, A. Pahl, C. M. Valina, C. Stratz, P. Schmiebusch, H.-P. Bestehorn, H. J. Buttner, et al. Cytochrome P450 2C19 681G>A Polymorphism and High On-Clopidogrel Platelet Reactivity Associated With Adverse 1-Year Clinical Outcome of Elective Percutaneous Coronary Intervention With Drug-Eluting or Bare-Metal Stents J. Am. Coll. Cardiol., May 20, 2008; 51(20): 1925 - 1934. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S. Small, N. A. Farid, C. D. Payne, G. J. Weerakkody, Y. G. Li, J. T. Brandt, D. E. Salazar, and K. J. Winters Effects of the Proton Pump Inhibitor Lansoprazole on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel J. Clin. Pharmacol., April 1, 2008; 48(4): 475 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. A. Farid, C. D. Payne, C. S. Ernest II, Y. G. Li, K. J. Winters, D. E. Salazar, and D. S. Small Prasugrel, a New Thienopyridine Antiplatelet Drug, Weakly Inhibits Cytochrome P450 2B6 in Humans J. Clin. Pharmacol., January 1, 2008; 48(1): 53 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Weerakkody, J. A. Jakubowski, J. T. Brandt, C. D. Payne, H. Naganuma, and K. J. Winters Greater Inhibition of Platelet Aggregation and Reduced Response Variability With Prasugrel Versus Clopidogrel: An Integrated Analysis Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2007; 12(3): 205 - 212. [Abstract] [PDF]
|
|
|
|
|
|
N. A. Farid, R. L. Smith, T. A. Gillespie, T. J. Rash, P. E. Blair, A. Kurihara, and M. J. Goldberg The Disposition of Prasugrel, a Novel Thienopyridine, in Humans Drug Metab. Dispos., July 1, 2007; 35(7): 1096 - 1104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Wickremsinhe, Y. Tian, K. J. Ruterbories, E. M. Verburg, G. J. Weerakkody, A. Kurihara, and N. A. Farid Stereoselective Metabolism of Prasugrel in Humans Using a Novel Chiral Liquid Chromatography-Tandem Mass Spectrometry Method Drug Metab. Dispos., June 1, 2007; 35(6): 917 - 921. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
