CYP3A4 mediated in vitro metabolism of vinflunine in human liver microsomes

Aim:To study the metabolism of vinflunine and the effects of selective cyto-chrome P-450(CYP450)inhibitors on the metabolism of vinflunine in human livermicrosomes.Methods:Individual selective CYP450 inhibitors were used to inves-tigate their effects on the metabolism of vinflunine and the principal CYP450 isoforminvolved in the formation of metabolites M1and M2in human liver microsomes.Results:Vinflunine was rapidly metabolized to 2 metabolites:M1and M2in humanliver microsomes.M1and M2were tentatively presumed to be the N-oxide metabo-lite or hydroxylated metabolite and epoxide metabolite of vinflunine,respectively.Ketoconazole uncompetitively inhibited the formation of M1,and competitivelyinhibited the formation of M2,while α-naphthoflavone,sulfaphenazole,diethyldithiocarbamate,tranylcypromine and quinidine bad little or no inhibitory effecton the formation of M1and M2.Conclusion:Vinflunine is rapidly metabolized inhuman liver microsomes,and CYP3A4 is the major human CYP450 involved in themetabolism of vinflunine.