Identification and Characterization of Efflux Transporters That Modulate the Subtoxic Disposition of Diclofenac and Its Metabolites.
Drug Metab Dispos
; 47(10): 1080-1092, 2019 10.
Article
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| MEDLINE
| ID: mdl-31399506
ABSTRACT
In the present work, in vivo transporter knockout (KO) mouse models were used to characterize the disposition of diclofenac (DCF) and its primary metabolites following a single subtoxic dose in mice lacking breast cancer resistance protein (Bcrp) or multidrug resistance-associated protein (Mrp)3. The results indicate that Bcrp acts as a canalicular efflux mediator for DCF, as wild-type (WT) mice had biliary excretion values that were 2.2- to 2.6-fold greater than Bcrp KO mice, although DCF plasma levels were not affected. The loss of Bcrp resulted in a 1.8- to 3.2-fold increase of diclofenac acyl glucuronide (DCF-AG) plasma concentrations in KO animals compared with WT mice, while the biliary excretion of DCF-AG increased 1.4-fold in WT versus KO mice. Furthermore, Mrp3 was found to mediate the basolateral transport of DCF-AG, but not DCF or 4'-hydroxy diclofenac. WT mice had DCF-AG plasma concentrations 7.0- to 8.6-fold higher than Mrp3 KO animals; however, there were no changes in biliary excretion of DCF-AG. Vesicular transport experiments with human MRP3 demonstrated that MRP3 is able to transport DCF-AG via low- and high-affinity binding sites. The low-affinity MRP3 transport had a V max and K m of 170 pmol/min/mg and 98.2 µM, respectively, while the high-affinity V max and K m parameters were estimated to be 71.9 pmol/min/mg and 1.78 µM, respectively. In summary, we offer evidence that the disposition of DCF-AG can be affected by both Bcrp and Mrp3, and these findings may be applicable to humans.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Diclofenaco
/
Subfamilia B de Transportador de Casetes de Unión a ATP
/
Glucurónidos
/
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Drug Metab Dispos
Asunto de la revista:
FARMACOLOGIA
Año:
2019
Tipo del documento:
Article