CYP3A4 mediated in vitro metabolism of vinflunine in human liver microsomes
Abstract
Aim: To study the metabolism of vinflunine and the effects of selective cytochrome
P-450 (CYP450) inhibitors on the metabolism of vinflunine in human liver
microsomes. Methods: Individual selective CYP450 inhibitors were used to investigate
their effects on the metabolism of vinflunine and the principal CYP450 isoform
involved in the formation of metabolites M1 and M2 in human liver microsomes.
Results: Vinflunine was rapidly metabolized to 2 metabolites: M1 and M2 in human
liver microsomes. M1 and M2 were tentatively presumed to be the N-oxide metabolite
or hydroxylated metabolite and epoxide metabolite of vinflunine, respectively.
Ketoconazole uncompetitively inhibited the formation of M1, and competitively
inhibited the formation of M2, while α-naphthoflavone, sulfaphenazole, diethyl
dithiocarbamate, tranylcypromine and quinidine had little or no inhibitory effect
on the formation of M1 and M2. Conclusion: Vinflunine is rapidly metabolized in
human liver microsomes, and CYP3A4 is the major human CYP450 involved in the
metabolism of vinflunine.
Keywords:
P-450 (CYP450) inhibitors on the metabolism of vinflunine in human liver
microsomes. Methods: Individual selective CYP450 inhibitors were used to investigate
their effects on the metabolism of vinflunine and the principal CYP450 isoform
involved in the formation of metabolites M1 and M2 in human liver microsomes.
Results: Vinflunine was rapidly metabolized to 2 metabolites: M1 and M2 in human
liver microsomes. M1 and M2 were tentatively presumed to be the N-oxide metabolite
or hydroxylated metabolite and epoxide metabolite of vinflunine, respectively.
Ketoconazole uncompetitively inhibited the formation of M1, and competitively
inhibited the formation of M2, while α-naphthoflavone, sulfaphenazole, diethyl
dithiocarbamate, tranylcypromine and quinidine had little or no inhibitory effect
on the formation of M1 and M2. Conclusion: Vinflunine is rapidly metabolized in
human liver microsomes, and CYP3A4 is the major human CYP450 involved in the
metabolism of vinflunine.