Involvement of human liver cytochrome P450 3A in vinblastine metabolism: drug interactions.
Vinblastine biotransformation was investigated by using a human liver microsomes library. The drug was converted into one major metabolite (M) upon incubation with the microsomes. A large interindividual variation in vinblastine metabolism was observed among the samples tested, with a 4.4 ratio between the lowest and the highest metabolic rates. The biotransformation of vinblastine followed Michaelis-Menten kinetics (Km = 6.82 +/- 0.27 microM and Vmax = 0.64 +/- 0.06 nmol/min/mg protein). The involvement of the cytochrome P450 3A subfamily in vinblastine metabolism was demonstrated by the following body of evidence: (a) the competitive inhibition of vinblastine biotransformation by cytochrome P450 3A specific probes with Ki values of 0.17, 22.5, 14.8, and 35.3 microM for ketoconazole, erythromycin, troleandomycin, and vindesine, respectively; (b) the immunoinhibition of vinblastine metabolism by polyclonal anti-cytochrome P450 3A antibodies; (c) the highly significant correlation between the level of cytochrome P450 3A determined by Western blots and vinblastine metabolism (r = 0.759, P < 0.001); (d) the highly significant correlation between erythromycin N-demethylase activity (mediated by cytochrome P450 3A) and vinblastine metabolism (r = 0.83, P < 0.001); (e) the significant correlation between the CYP3A4 mRNA level and vinblastine metabolism (r = 0.60, P < 0.1). Although vincristine and navelbine (members of the Vinca alkaloid family) also inhibit the metabolism of vinblastine, suggesting the involvement of the cytochrome subfamily in their respective metabolisms, other anticancer drugs currently associated with vinblastine in chemotherapy (etoposide, Adriamycin, lomustine, and teniposide) also interfere with vinblastine biotransformation. These metabolic drug interactions may alter the antitumor activity and/or toxicity of the drug during anticancer chemotherapy.
Zhou-Pan
X R
XR
Institut National de la Santé et de la Recherche Médicale, Unité 278, Faculté de pharmacie, Marseille, France.
Sérée
E
E
Zhou
X J
XJ
Placidi
M
M
Maurel
P
P
Barra
Y
Y
Rahmani
R
R
D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000494:pharmacology; D001483:Base Sequence; D001667:Binding, Competitive; D001711:Biotransformation; D015153:Blotting, Western; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004347:Drug Interactions; D004917:Erythromycin / Q000494:pharmacology; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D005810:Multigene Family; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger / Q000378:metabolism; D014217:Troleandomycin / Q000494:pharmacology; D014747:Vinblastine / Q000378:metabolism*; D014751:Vindesine / Q000494:pharmacology
D000906:Antibodies; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D014747:Vinblastine; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D007654:Ketoconazole; D014751:Vindesine