Enhanced metabolic activation of and platelet response to clopidogrel in T-cell deficient mice through induction of Cyp2c and Cyp3a and inhibition of Ces1

Background: T cells and platelets reciprocally coordinate mutual functions through crosstalk or interaction. However, it is not known whether metabolic activation of and platelet response to clopidogrel could be changed if T cells were deficient or impaired in some cases and if any, how it would work.

Objectives: To dissect potential changes in platelet responses to and metabolic activation of clopidogrel in case of T-cell deficiency and to elucidate their mechanisms involved.

Methods: BALB/c athymic nude mice or euthymic mice (controls) pretreated with cyclosporine A (CsA), thymosin α1 (Tα1), or their combination were used to investigate changes in ADP-induced platelet activation and aggregation, systemic exposure of clopidogrel and its metabolites, and mRNA/protein expression as well as activity levels of clopidogrel-metabolizing enzymes in the liver, respectively.

Results: Nude mice exhibited significantly enhanced antiplatelet effects of clopidogrel due to increased formation of clopidogrel active metabolite in the liver, where Enzyme activity levels of Cyp2c and Cyp3a were significantly elevated compared with control mice. Further, effects of CsA pretreatment on the metabolism of clopidogrel in euthymic mice were identical to those seen in athymic mice. As expected, concomitant use of Tα1 reversed all observed effects of CsA on clopidogrel metabolism and relevant metabolic enzymes.

Conclusions: T-cell deficiency or suppression enhances the antiplatelet effects of clopidogrel due to boosted metabolic activation of clopidogrel in the liver through dramatic induction of Cyp2c and Cyp3a in mice, suggesting that the metabolism of substrate drugs of CYP2C and CYP3A may be enhanced by T-cell impairment.

T cell; clopidogrel; cyclosporine A; interplay; metabolism; platelet.