Received for publication November 1, 2005.
Revised December 16, 2005.
Accepted for publication January 11, 2006.

Interactions of Two Major Metabolites of Prasugrel, a Thienopyridine Antiplatelet Agent, with the Cytochromes P450

Abstract

The biotransformation of prasugrel to R-138727 involves rapid de-esterification to R-95913 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 (K_m 21-30 µM), consistent with a single enzyme predominating, were observed following 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<.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>CYP2C19CYP2C9>CYP2D6. A monoclonal antibody to CYP2B6 and the CYP3A inhibitor ketoconazole substantially inhibited R-138727 formation, while 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 abilities 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 K_i values ranging from 7.2 µM to 82 µM but did not inhibit CYP1A2. These K_i 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 co-administered drugs.

Key words: CYP2B, CYP3A, cytochrome P450, drug-drug interactions, enzyme kinetics, glutathione, human CYP enzymes, in vitro-in vivo scaling, liver microsomes, prodrugs

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