Characterization of human cytochrome P450 isoenzymes involved in the metabolism of vinorelbine

Abstract

Vinorelbine (VRL) (IV Navelbine) is a semi-synthetic vinca alkaloid, used in therapeutics for the treatment of non-small-cell lung cancer and advanced breast cancer. The aim of this study was to characterize the cytochrome P450 (CYP) isoenzymes involved in VRL metabolism. VRL was incubated at 1.28 x 10(-5) m for 90 min with human hepatic microsomes prepared from 14 donors (one woman and 13 men aged from 27 to 76 years old) and characterized for CYP1A2, CYP2D6, CYP2E1 and CYP3A4 activities. A four-combined-approach study was performed, including correlation between CYP activities and VRL metabolism among the 14 batches of microsomes, inhibition of VRL biotransformation by isoform-selective substrates and by specific inhibitory antibodies, and incubation with supersomes. Analysis of unchanged VRL and its metabolites was performed using an HPLC method coupled with both radioactive and UV detections. No correlation between CYP1A2 or CYP2E1 and VRL metabolism was observed in the 14 batches of microsomes used. A correlation was shown between VRL metabolism and CYP3A4 activity as determined with the dextromethorphan N-demethylase and nifedipine oxidase activities (r(2)=0.80 and 0.59, respectively). These results were strengthened by a correlation between the metabolism extent of VRL and CYP3A4 protein content determined by immunoblotting (r(2)=0.75). Furthermore, VRL biotransformation was inhibited by troleandomycine, the CYP3A4-specific inhibitor substrate (80% of inhibition) and by anti-CYP3A antibodies (36% of inhibition). On the contrary, a low correlation with CYP2D6 activity as determined by dextrometorphan O-demethylation (r(2)=0.31) was established. CYP2D6 supersomes did not metabolize the drug whereas 63.4% of VRL were metabolized by microsomes overexpressing CYP3A4 isoform. These data indicated that CYP3A4 is the main enzyme involved in the hepatic metabolism of VRL in human, whereas CYP2D6 is not involved.

Metabolism pathway of vinorelbine (Navelbine®) in human: Characterisation of the metabolites by HPLC–MS/MS

“…This was consistent with in vitro studies showing that CYP3A4 was the main isoenzyme involved in the metabolism of VRL [9,23].…”

Oral versus intravenous vinorelbine: clinical safety profile

“…Unchanged vinorelbine was the major compound recovered in faeces (30 -50% of the dose). All metabolites were formed trough cytochrome P450 CYP 3A4 except 4-O-deacetylvinorelbine [21,22]. All the metabolites but one -4-O-deacetylvinorelbine -are inactive.…”

Molecular Pharmacokinetics of Catharanthus (Vinca) Alkaloids

“…Two articles have reported the identification of the CYP involved in the in vitro metabolism of vinorelbine 21,22 . Kajita et al 21 first observed additional chromatographical peaks corresponding to polar metabolites of unknown structure after the incubation of vinorelbine (0.5 μM) using human liver microsomes and recombinant CYP3A4.…”