CYP3A4 mediated in vitro metabolism of vinflunine in human liver microsomes.
OBJECTIVE
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 M(1) and M(2) in human liver microsomes.


RESULTS
Vinflunine was rapidly metabolized to 2 metabolites: M(1) and M(2) in human liver microsomes. M(1) and M(2) were tentatively presumed to be the N-oxide metabolite or hydroxylated metabolite and epoxide metabolite of vinflunine, respectively. Ketoconazole uncompetitively inhibited the formation of M(1), and competitively inhibited the formation of M(2), while alpha-naphthoflavone, sulfaphenazole, diethyl dithiocarbamate, tranylcypromine and quinidine had little or no inhibitory effect on the formation of M(1) and M(2).


CONCLUSIONS
Vinflunine is rapidly metabolized in human liver microsomes, and CYP3A4 is the major human CYP450 involved in the metabolism of vinflunine.
Zhao
Xiao-Ping
XP
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Zhong
Jiao
J
Liu
Xiao-Quan
XQ
Wang
Guang-Ji
GJ
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001571:Benzoflavones / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004050:Ditiocarb / Q000494:pharmacology; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015394:Molecular Structure; D011802:Quinidine / Q000494:pharmacology; D013426:Sulfaphenazole / Q000494:pharmacology; D014191:Tranylcypromine / Q000494:pharmacology; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
D001571:Benzoflavones; D065692:Cytochrome P-450 CYP3A Inhibitors; D013426:Sulfaphenazole; D014191:Tranylcypromine; C111217:vinflunine; D014747:Vinblastine; C011512:alpha-naphthoflavone; D004050:Ditiocarb; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D011802:Quinidine; D007654:Ketoconazole