Cytochrome clopidogrel

Thienopyridines are inactive in vitro. Absorbed in the upper gastrointestinal tract, clopidogrel is converted to an active metabolite by the hepatic cytochrome P450 system (3,4). 

Lau WC, Gurbel PA, Watkins PB, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation 2004 109 166-171. 

Savi R Combalbert J, Gaich C, et al, The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450-IA. Thromb Haemost 1994 72 313-317,... 

Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS (2009) Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 360 354-362... 

Turpeinen M, Tolonen A, Uusitalo J, et al. Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Cbn Pharmacol Ther 2005 77 553-559. 

Clarke, T.A. and Waskell, L.A. (2003) The metabolism of clopidogrel is catalyzed by human cytochrome P450 3A and is inhibited by atorvastatin. Drug Metabolism and Disposition The Biological Fate of Chemicals, 31, 53-59. 

Hulot, J.-S., Bura, A., Villard, E., Azizi, M., Remones, V., Goyenvalle, C., Aiach, M., Lechat, P., and Gaussem, R (2006) Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 108 (7), 2244-2247. 

M. Schwab, and U.M. Zanger (2003). Clopidogrel and ticlopidine are specific mechanism-based inhibitors of human cytochrome P450 2B6. Proceedings of the 13th International Conference on Cytochromes P450, Prague, Czech Republic, p. SI 19. 

In the cases where rhabdomyolysis developed when clopidogrel was added to treatment with eielosporin and a statin it was thought that the addition of clopidogrel (which may also inhibit the cytochrome P450 enzyme system) may have destabilised the delicate metabolic equilibrium between the statins and eielosporin precipitating the development of rhabdomyolysis. 

Although the electron-rich thiophene may lead to toxicity, the metabolic chemistry of thiophene can also lead to desirable therapeutic effects as in the case of clopidogrel (Plavix). The parent compound is oxidized by cytochrome P-450, and further oxidation in the presence of water... 

Zhang H, Amunugama H, Ney S, Cooper N, Hollenberg PF (2011) Mechanism-based inactivation of human cytochrome P450 2B6 by clopidogrel leads to both covalent modification of cysteinyl residue 475 and loss of heme. Mol Pharmacol 80 839-847... 

Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A (2010) Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos 38 92-99... 

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