Coadministration of p-glycoprotein modulators on loperamide pharmacokinetics and brain distribution

Rita Nieto Montesinos, Brice Moulari, Jessica Gromand, Arnaud Beduneau, Alf Lamprecht, Yann Pellequer

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

42 Citas (Scopus)

Resumen

The efflux transporter P-glycoprotein, expressed at high levels at the blood-brain barrier, exerts a profound effect on the disposition of various therapeutic compounds in the brain. A rapid and efficient modulation of this efflux transporter could enhance the distribution of its substrates and thereby improve central nervous system pharmacotherapies. This study explored the impact of the intravenous coadministration of two P-glycoprotein modulators, tariquidar and elacridar, on the pharmacokinetics and brain distribution of loperamide, a P-glycoprotein substrate probe, in rats. After 1 hour postdosing, tariquidar and elacridar, both at a dose of 1.0 mg/kg, increased loperamide levels in the brain by 2.3- and 3.5-fold, respectively. However, the concurrent administration of both P-glycoprotein modulators, each at a dose of 0.5 mg/kg, increased loperamide levels in the brain by 5.8-fold and resulted in the most pronounced opioid-induced clinical signs. This phenomenon may be the result of a combined noncompetitive modulation by tariquidar and elacridar. Besides, the simultaneous administration of elacridar and tariquidar did not significantly modify the pharmacokinetic parameters of loperamide. This observation potentially allows the concurrent use of low but therapeutic doses of P-gp modulators to achieve full inhibitory effects.

Idioma originalInglés
Páginas (desde-hasta)700-706
Número de páginas7
PublicaciónDrug Metabolism and Disposition
Volumen42
N.º4
DOI
EstadoPublicada - abr. 2014
Publicado de forma externa

Huella

Profundice en los temas de investigación de 'Coadministration of p-glycoprotein modulators on loperamide pharmacokinetics and brain distribution'. En conjunto forman una huella única.

Citar esto