The effect of rifampin on the pharmacokinetics of vinorelbine in the micropig
Leveque, D.; Wisniewski, S.; Renault, C.; Peter, J.Daniel.; Le Corre, P.; Monteil, H.; Jehl, Fçois.
Anticancer Research 23(3b): 2741-2744
2003
ISSN/ISBN: 0250-7005 PMID: 12894568 Document Number: 557097
Background: Vinorelbine has been shown to be metabolised by CYP3A4 in vitro. To evaluate the impact of CYP3A in the disposition of vinorelbine in vivo, we compared the kinetics of the alkaloid given intravenously alone and combined with rifampin, a potent CYP3A inducer, in the micropig. Animals and Methods: Four healthy Yucatan micropigs, about 20kg, received a first infusion of vinorelbine (0.5mg/kg). During the next week they were injected rifampin (600mg daily) and a second vinorelbine infusion (0.5mg/kg) on the 7th day of rifampin dosing. Serum concentrations of vinorelbine and rifampin were measured by high performance liquid chromatography. Results: The mean peak concentrations of vinorelbine were 274.2ng/ml(Standard Deviation or SD: 90) and 458ng/ml (SD: 448), the mean areas under the serum concentration-time curve were 8,344ng.min.ml-1 (SD: 2,604) and 14,093ng/ml.min-1 (SD: 10,000) and the total clearances were 1.146l/min (SD: 0.333) and 1.003l/min (SD: 0.714) when the Catharanthus alkaloid was given alone or was combined with rifampin, respectively. Conclusion: We did not observe an increase in vinorelbine elimination by rifampin related to a CYP3A induction in an animal model physiologically close to humans. Although the number of animals was small, these results suggest that CYP3A metabolism constitutes a minor pathway of elimination of intravenous vinorelbine in the micropig.