The role of p-glycoprotein in limiting brain penetration of the peripherally acting anticholinergic overactive bladder drug trospium chloride.
The aim of the present study was to characterize the role of the drug-efflux transporter P-glycoprotein (P-gp) for the disposition of trospium chloride, a widely used anticholinergic drug for the treatment of overactive bladder. P-gp-deficient mdr1a,b(-/-) knockout mice were given either 1 mg/kg trospium chloride orally or 1 mg/kg intravenously to analyze brain penetration, intestinal secretion, and hepatobiliary excretion of the drug. The concentrations of trospium chloride in the brain were up to 7 times higher in the mdr1a,b(-/-) knockout mice compared with wild-type mice (p < 0.05), making P-gp a limiting factor for the blood-brain barrier penetration of this drug. Moreover, the residence time of the drug in the central nervous system was significantly prolonged in mdr1a,b(-/-) knockout mice. Apart from the blood-brain barrier, P-gp also had significant effects on the overall pharmacokinetics of trospium chloride. In the mdr1a,b(-/-) knockout mice, hepatobiliary excretion and intestinal secretion were significantly reduced compared with the wild-type mice. Our study indicates that the multidrug resistance transporter P-gp is a major determinant for the distribution of trospium chloride in the body and highly restricts its entry into the brain.
Geyer
Joachim
J
Institute of Pharmacology and Toxicology, Justus Liebig University of Giessen, Frankfurter Str. 107, 35392 Giessen, Germany. Joachim.M.Geyer@vetmed.uni-giessen.de
Gavrilova
Olga
O
Petzinger
Ernst
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001561:Benzilates; D001692:Biological Transport / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D009662:Nortropanes / Q000494:pharmacology* / Q000652:urine; D014018:Tissue Distribution / Q000187:drug effects; D053201:Urinary Bladder, Overactive / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001561:Benzilates; D002250:Carbon Radioisotopes; D006023:Glycoproteins; D009662:Nortropanes; C003330:trospium chloride