THE ANTIAGGREGATING ACTIVITY OF CLOPIDOGREL IS DUE TO A METABOLIC-ACTIVATION BY THE HEPATIC CYTOCHROME P450-1A

Clopidogrel and ticlopidine are two well known selective anti-ADP agen ts which are inactive in vitro and must be administered in vivo to ful ly exhibit their antiaggregating and antithrombotic effects. Since pre vious studies have clearly demonstrated that the activation steps take place in the liver, we examined the effect of specific induction or i nhibition of cytochrome P450 subfamilies on the antiaggregating activi ty of clopidogrel. SKF 525-A, a global cytochrome P450 inhibitor, dram atically decreased the antiaggregating effect of clopidogrel, therefor e indicating that cytochrome P450 enzymes are involved in the hepatic activation of clopidogrel. The efficacy of clopidogrel was increased i n animals pretreated with 3-methylcholanthrene and beta-naphthoflavone , indicating that the cytochrome P450-1A subfamily pathway was mainly involved in the activating metabolism of clopidogrel. The use of speci fic antibodies directed against the various cytochrome P450 subfamilie s ascertained this observation.