Emmanuelle Comets, France Mentré and François Gimenez
INSERM
Objectives: Mefloquine is a chiral neurotoxic antimalarial agent showing stereoselective brain uptake in humans and rats. It is a substrate and an inhibitor of the efflux protein P-glycoprotein. We investigated the stereoselective uptake and efflux of mefloquine in mice, and the consequences of the combination with an efflux protein inhibitor, elacridar (GF120918) on its brain transport.
Methods: Racemic mefloquine (25mg/kg) was administered intraperitoneally to OF1 female mice, with or without elacridar (10mg/kg). Six to seven mice were sacrificed at each of 11sampling times between 30min and 168h after administration. Blood and brain concentrations of mefloquine enantiomers were determined using liquid chromatography. We modelled the pharmacokinetics of the two enantiomers jointly in blood and brain using non linear regression weighted by the empirical variance.Results: A three-compartment model with zero-order absorption from the injection site was found to best represent the pharmacokinetics of both enantiomers in blood and brain. (-)Mefloquine had a lower blood and brain apparent volume of distribution and a lower efflux clearance from the brain, resulting in a larger brain/blood ratio compared to (+)mefloquine. Elacridar did not modify blood concentrations or the elimination rate from blood for either enantiomers. However, cerebral AUC of both enantiomers were increased after elacridar administration, with a stronger effect on (+)mefloquine. The efflux clearance from the brain decreased for both enantiomers, with a larger decrease for (+)mefloquine.
Conclusion: After administration of racemic mefloquine in mice, blood and brain pharmacokinetics are stereoselective, (+)mefloquine being excreted from brain more rapidly than its antipode, showing that mefloquine is a substrate of efflux proteins and that mefloquine enantiomers undergo efflux in a stereoselective manner. Moreover, pretreatment with elacridar reduced the brain efflux clearances with a more pronounced effect on (+)mefloquine.
Reference: PAGE 13 (2004) Abstr 508 [www.page-meeting.org/?abstract=508]
Poster: poster