The role of p-glycoprotein in limiting brain penetration of the peripherally acting anticholinergic overactive bladder drug trospium chloride.
Drug Metab Dispos
; 37(7): 1371-4, 2009 Jul.
Article
em En
| MEDLINE
| ID: mdl-19389858
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transporte Biológico
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Encéfalo
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP
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Bexiga Urinária Hiperativa
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Camundongos
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Nortropanos
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article