title: 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.
authors.affiliation: Département de Pharmacie Clinique, EA 2706, Faculté de Pharmacie, 5, rue Jean Baptiste Clément, 92296 Châtenay-Malabry, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Barraud de Lagerie
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Comets
authors.forename: Céline
authors.initials: C
authors.lastname: Gautrand
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandez
authors.forename: Daniel
authors.initials: D
authors.lastname: Auchere
authors.forename: Eric
authors.initials: E
authors.lastname: Singlas
authors.forename: France
authors.initials: F
authors.lastname: Mentre
authors.forename: François
authors.initials: F
authors.lastname: Gimenez
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics*; D000166:Acridines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D005260:Female; D007274:Injections, Intraperitoneal; D015767:Mefloquine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D051379:Mice; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D044005:Tetrahydroisoquinolines; C083501:Elacridar; D015767:Mefloquine