Elsevier

Biochemical Pharmacology

Volume 45, Issue 4, 24 February 1993, Pages 853-861
Biochemical Pharmacology

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

https://doi.org/10.1016/0006-2952(93)90169-WGet rights and content

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 inter-individual 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 μM, 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 μM 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 μM 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.

References (33)

  • MJ Ratain et al.

    Interpatient and intrapatient variability in vinblastine pharmacokinetics

    Clin Pharmacol Ther

    (1987)
  • DV Jackson et al.

    Pharmacokinetics of vincristine infusion

    Cancer Treat Rep

    (1981)
  • DV Jackson et al.

    Pharmacokinetics of vindesine bolus and infusion

    Cancer Chemother Pharmacol

    (1984)
  • T Ohnuma et al.

    Pharmacokinetics of vindesine given as an intravenous bolus and 24-hour infusion in humans

    Cancer Res

    (1985)
  • K Lu et al.

    Clinical pharmacokinetics of vinblastine by continuous intravenous infusion

    Cancer Res

    (1983)
  • R Rahmani et al.

    Clinical pharmacokinetics of vindesine: repeated treatments by intravenous bolus injections

    Eur J Cancer Clin Oncol

    (1984)
  • Cited by (89)

    • Rapid quantification of vincristine in mouse plasma using ESI-LC-MS/MS: Application to pharmacokinetic studies

      2021, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences
      Citation Excerpt :

      It has been speculated that a critical determinant of this variability is associated with differential expression of polymorphic drug-metabolizing enzymes and/or transporters at sites of elimination. Evidence from in vitro studies has indicated that vincristine undergoes cytochrome P-450 3A (CYP3A)-mediated metabolism [9,10], with CYP3A5 contributing to 75% of the intrinsic clearance of vincristine [11–13]. Interestingly, the incidence of vincristine-induced peripheral neuropathy appears to be lower in patients who functionally express CYP3A5 [14,15], and is increased in patients concurrently treated for fungal infections [16] with azole antifungals that potently inhibit CYP3A-mediated metabolism, such as ketoconazole [17].

    • Structural perspectives of the CYP3A family and their small molecule modulators in drug metabolism

      2019, Liver Research
      Citation Excerpt :

      Chemotherapeutics are one class of drug that is largely implicated in CYP3A interactions.25 For example, the microtubule-destabilizing vinca alkaloids vincristine, vinblastine, and vindesine are substrates of CYP3A4, CYP3A5, and CYP3A7.26,27 Other antimitotics of the same parent class, such as the taxanes paclitaxel and docetaxel, are also metabolized by these enzymes.28,29

    • Cancer chemotherapy

      2013, Drug-Induced Liver Disease
    View all citing articles on Scopus
    View full text