Increased uptake of quinine into the brain by inhibition of P-glycoprotein.
The impact of P-glycoprotein (P-gp) on the distribution of quinine between brain and plasma was studied experimentally in mice. Administration of quinine (20mg/kg, i.v.) to mdrla knockout mice resulted in enhanced brain concentrations of quinine as compared to the wild-type mice (7.9+/-1.4 microg/g versus 1.6+/-0.8 microg/g, respectively). Quinine concentrations and quinine-to-3-hydroxyquinine ratio in plasma were similar in normal and P-gp-deficient mice. The effect of intravenously administered drugs before quinine (20mg/kg, i.v.) was evaluated on brain uptake and biotransformation of quinine in mice. Cyclosporine A (50 mg/kg), erythromycine (40 mg/kg), verapamil (5mg/kg) or mefloquine (20 mg/kg) increased the brain-to-plasma quinine concentration ratio (by factors of 3.8-, 1.8-, 1.9- and 2.5-fold, respectively) and the quinine-to-3-hydroxyquinine ratio in plasma (by factors 2.1-, 3.7-, 1.8- and 2.0-fold, respectively). After cinchonine (40 mg/kg) and halofantrine (40 mg/kg) pre-treatment, the brain-to-plasma ratio for quinine increased by factor of 2.3 and 1.8, respectively without changes of quinine or metabolite concentrations in plasma. Doxycycline (20 mg/kg), artesunate (50 mg/kg) or artemether (50 mg/kg) did not alter quinine disposition. These results confirm in vivo that quinine is a substrate for mdr1a P-gp. Drug associations led not only to metabolic interactions but also increased quinine uptake by tissues protected by P-gp. Such interactions may have implications for the improvement of chemotherapy but should be also taken into account for potential enhancement of adverse effects.
Pussard
Eric
E
Service de Pharmacologie, Hôpital de Bicêtre et faculté de Médecine Paris-Sud, France. eric.pussard@bct.aphp.fr
Merzouk
Mourad
M
Barennes
Hubert
H
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D003627:Data Interpretation, Statistical; D051379:Mice; D018345:Mice, Knockout; D011803:Quinine / Q000097:blood / Q000493:pharmacokinetics*
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; C095122:multidrug resistance protein 3; D011803:Quinine