Back to Search
Start Over
Cerebral uptake of mefloquine enantiomers with and without the P-gp inhibitor elacridar (GF1210918) in mice.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2004 Apr; Vol. 141 (7), pp. 1214-22. Date of Electronic Publication: 2004 Mar 15. - Publication Year :
- 2004
-
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.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 administration & dosage
Acridines administration & dosage
Acridines chemistry
Animals
Area Under Curve
Blood-Brain Barrier chemistry
Blood-Brain Barrier drug effects
Blood-Brain Barrier metabolism
Female
Injections, Intraperitoneal
Mefloquine administration & dosage
Mefloquine chemistry
Metabolic Clearance Rate drug effects
Metabolic Clearance Rate physiology
Mice
Tetrahydroisoquinolines administration & dosage
Time Factors
ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily B, Member 1 pharmacokinetics
Acridines pharmacokinetics
Brain metabolism
Mefloquine pharmacokinetics
Stereoisomerism
Tetrahydroisoquinolines pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 0007-1188
- Volume :
- 141
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 15023856
- Full Text :
- https://doi.org/10.1038/sj.bjp.0705721