RT Journal Article
SR Electronic
T1 The Role of P-Glycoprotein in Limiting Brain Penetration of the Peripherally Acting Anticholinergic Overactive Bladder Drug Trospium Chloride
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1371
OP 1374
DO 10.1124/dmd.109.027144
VO 37
IS 7
A1 Joachim Geyer
A1 Olga Gavrilova
A1 Ernst Petzinger
YR 2009
UL http://dmd.aspetjournals.org/content/37/7/1371.abstract
AB 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.