Human liver microsomal cytochrome P450 3A isozymes mediated vindesine biotransformation. Metabolic drug interactions.

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Zhou XJ, Zhou-Pan XR, Gauthier T, Placidi M, Maurel P, Rahmani R

Human liver microsomal cytochrome P450 3A isozymes mediated vindesine biotransformation. Metabolic drug interactions.

Biochem Pharmacol. 1993 Feb 24;45(4):853-61.

PubMed ID

8452560 [ View in PubMed

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Abstract

Vindesine biotransformation was investigated using a bank of human liver microsomes. The drug was converted into one major metabolite (M) upon incubation with the microsomes. Large interindividual variations were observed: vindesine biotransformation rates ranged from 1.2 to 12.9 pmol/min/mg protein. Vindesine metabolic processes followed Michaelis-Menten kinetics: Km = 24.7 +/- 9.4 microM, Vmax = 1.5 +/- 0.8 nmol/min/mg protein. The involvement of human cytochrome P450 3A isozymes in vindesine metabolism was demonstrated by: (1) competitive inhibition of vindesine biotransformation by compounds known to be specifically metabolized by human cytochrome P450 3A. Apparent Ki values were 3.6, 17.9 and 19.8 microM for quinidine, troleandomycin and erythromycin, respectively; (2) immunoinhibition of vindesine metabolism by polyclonal anti-P450 3A antibody; (3) significant correlation between immunoquantified P450 3A and vindesine biotransformation (r = 0.800, P < 0.001); and (4) significant correlation between erythromycin N-demethylase activity, which was supported by P450 3A in humans, and vindesine biotransformation (r = 0.853, P < 0.001). Other vinca alkaloids also exerted an inhibitory effect on vindesine biotransformation with apparent Ki values of 3.8, 10.6 and 19.2 microM for vinblastine, vincristine and navelbine, respectively, suggesting a possible involvement of the same cytochrome subfamily in their hepatic metabolism. Moreover, a number of anticancer drugs currently associated with the vinca alkaloids, such as teniposide, etoposide, doxorubicin, lomustine, folinic acid and mitoxantrone, significantly inhibited vindesine biotransformation.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Doxorubicin	Cytochrome P450 3A4	Protein	Humans	No	Substrate Inhibitor	Details
Mitoxantrone	Cytochrome P450 3A4	Protein	Humans	Unknown	Inhibitor	Details
Vincristine	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate	Details
Vindesine	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate	Details

Drug Interactions

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drugs	Interaction
Integrate drug-drug interactions in your software
Vinblastine Josamycin	The serum concentration of Vinblastine can be increased when it is combined with Josamycin.
Vinblastine Tylvalosin	The serum concentration of Vinblastine can be increased when it is combined with Tylvalosin.
Vinblastine Mepartricin	The serum concentration of Vinblastine can be increased when it is combined with Mepartricin.
Vinblastine Tilmicosin	The serum concentration of Vinblastine can be increased when it is combined with Tilmicosin.
Vinblastine Tylosin	The serum concentration of Vinblastine can be increased when it is combined with Tylosin.

Food Interactions

Drug	Interaction
Vindesine	Exercise caution with grapefruit products. Vindesine is metabolized by CYP3A4, and grapefruit inhibits CYP3A4 metabolism, which may increase vindesine serum levels.
Vindesine	Exercise caution with St. John's Wort. Vindesine is metabolized by CYP3A4 and this herb induces CYP3A4 metabolism, which may reduce vindesine serum levels.