The effect of rifampin on the pharmacokinetics of vinorelbine in the micropig.
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.


METHODS
Four healthy Yucatan micropigs, about 20 kg, received a first infusion of vinorelbine (0.5 mg/kg). During the next week they were injected rifampin (600 mg daily) and a second vinorelbine infusion (0.5 mg/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 274.2 ng/ml (Standard Deviation or SD: 90) and 458 ng/ml (SD: 448), the mean areas under the serum concentration-time curve were 8,344 ng.min.ml-1 (SD: 2,604) and 14,093 ng/ml.min-1 (SD: 10,000) and the total clearances were 1.146 l/min (SD: 0.333) and 1.003 l/min (SD: 0.714) when the Catharanthus alkaloid was given alone or was combined with rifampin, respectively.


CONCLUSIONS
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.
Leveque
Dominique
D
Hôpital de Hautepierre, Institut de Bactériologie, Laboratoire d'antibiologie, 67000 Strasbourg, France. dominique.leveque@chru-strasbourg.fr
Wisniewski
Sandra
S
Renault
Corinne
C
Peter
Jean Daniel
JD
Le Corre
Pascal
P
Monteil
Henri
H
Jehl
François
F
D000818:Animals; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D012293:Rifampin / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D000077235:Vinorelbine
D000904:Antibiotics, Antitubercular; D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077235:Vinorelbine; D012293:Rifampin