Selective Metabolism of Vincristine in Vitro by Cyp3a5

Abstract

ABSTRACT:Clinical outcomes of vincristine therapy, both neurotoxicity and efficacy, are unpredictable, and the reported pharmacokinetics of vincristine have considerable interindividual variability. In vitro and in vivo data support a dominant role for CYP3A enzymes in the elimination of vincristine. Consequently, genetic polymorphisms in cytochrome P450 (P450) expression may contribute to the interindividual variability in clinical response, but the contributions of individual P450s and the primary pathways of vincristine metabolism have not been defined. In the present study, vincristine was incubated with a library of cDNA-expressed P450s, and the major oxidative metabolites were identified. CYP3A4 and CYP3A5 were the only P450s to support substantial loss of parent drug and formation of the previously unidentified, major metabolite (M1). The structure of M1, arising as a result of an oxidative cleavage of the piperidine ring of the dihydro-hydroxycatharanthine unit of vincristine, was conclusively established after conversion to suitable derivatives followed by spectroscopic analysis, and a new pathway for vincristine metabolism is proposed. CYP3A5 was more efficient in catalyzing the formation of M1 compared with CYP3A4 (9-to 14-fold higher intrinsic clearance for CYP3A5). The formation of M1 was stimulated (3-fold) by the presence of coexpressed cytochrome b 5 , but the relative efficiencies of M1 formation by CYP3A4 and CYP3A5 were unaffected. Our findings demonstrate that in contrast to most CYP3A biotransformations, the oxidation of vincristine is considerably more efficient with CYP3A5 than with CYP3A4. We conclude that common genetic polymorphisms in CYP3A5 expression may contribute to the interindividual variability in the systemic elimination of vincristine.

Drug Interactions of Thalidomide with Midazolam and Cyclosporine A: Heterotropic Cooperativity of Human Cytochrome P450 3A5

“…In preliminary experiments, however, low concentrations of thalidomide did not activate the oxidative cleavage of vincristine (catalyzed by P450 3A5 or liver microsomes with CYP3A5*1/*3) (results not shown). The K m values (for the major oxidative cleavage of vincristine catalyzed by P450 3A5) have been reported to be 13 to 17 M (Dennison et al, 2006). Because vincristine is a large molecule and has high P450 3A5 affinity, these present results may be interpreted that thalidomide could not dock in P450 3A5 before vincristine.…”

Metabolism of Quetiapine by CYP3A4 and CYP3A5 in Presence or Absence of Cytochrome B5

“…For instance, Klees et al (2005) reported a 5-to 7-fold increase in CL int of alfentanil in CYP3A4 microsomes coexpressed with cytochrome b 5 . Furthermore, the formation of the major metabolite of vincristine through CYP3A5 was stimulated (3-fold) by the presence of coexpressed cytochrome b 5 (Dennison et al, 2006). The conflicting results indicate a substrate-dependent impact of cytochrome b 5 , and this should be further evaluated for more substrates.…”

Synergistic interaction of ABCB1 and ABCG2 polymorphisms predicts the prevalence of toxic encephalopathy during anticancer chemotherapy

“…The two transporters may also have substrates with mutually complementing neurotoxic effects. The routes of metabolism and the intermediary metabolites of some cytostatic drugs are not yet fully discovered, although important new data are emerging nowadays, 29 and transport properties of possibly neurotoxic metabolites of chemotherapy agents are unexplored. Such metabolites might also play a role in the consequences of interindividual differences of efflux transporter activities.…”