Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice

Abstract

1. 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. 2. 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. 3. Racemic mefloquine (25 mg kg(-1)) was administered intraperitoneally with or without elacridar (10 mg kg(-1)). Six to seven mice were killed at each of 11 time-points between 30 min and 168 h after administration. Blood and brain concentrations of mefloquine enantiomers were determined using liquid chromatography. 4. 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(inf) of both enantiomers were increased, with a stronger effect on (+)mefloquine. The efflux clearance from the brain decreased for both enantiomers, with a larger decrease for (+)mefloquine. 5. 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.

Figure 1

Three-compartment model used to describe the pharmacokinetics of the two enantiomers of mefloquine in mouse blood and brain.

Figure 2

Concentrations versus time in blood for both enantiomers of mefloquine (MQ) after a single intraperitoneal administration of 25 mg kg⁻¹ of racemic mefloquine. The plots are separated by group (left, mefloquine alone; right, mefloquine coadministered with the inhibitor). In each plot, the predicted and observed concentrations are shown for (+)MQ (observations: triangles, predictions: full line) and (−)MQ (observations: x; predictions: dotted line).

Figure 3

Concentrations versus time in brain for both enantiomers of mefloquine (MQ) after a single intraperitoneal administration of 25 mg kg⁻¹ of racemic mefloquine. The plots are separated by group (left, mefloquine alone; right, mefloquine coadministered with the inhibitor). In each plot, the predicted and observed concentrations are shown for (+)MQ (observations: triangles, predictions: full line) and (−)MQ (observations: x; predictions: dotted line).

Figure 4

Mean brain/whole blood concentration ratios (s.d.) for racemic mefloquine (Racemic) (circle, full line) and the enantiomers of mefloquine (+)MQ (triangle, dotted line) and (−)MQ (x, dotted line) after a single intraperitoneal administration of 25 mg kg⁻¹ of racemic mefloquine. The plots are separated by group (left, mefloquine alone; right, mefloquine coadministered with the inhibitor).