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Impact of Direction of Transport on the Evaluation of Inhibition Potencies of Multidrug and Toxin Extrusion Protein 1 Inhibitors.
Saito, Asami; Ishiguro, Naoki; Takatani, Masahito; Bister, Bojan; Kusuhara, Hiroyuki.
Afiliação
  • Saito A; Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (A.S., N.I, M.T., B.B.) and Laboratory of Molecular Pharmaceutics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K.).
  • Ishiguro N; Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (A.S., N.I, M.T., B.B.) and Laboratory of Molecular Pharmaceutics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K.).
  • Takatani M; Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (A.S., N.I, M.T., B.B.) and Laboratory of Molecular Pharmaceutics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K.).
  • Bister B; Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (A.S., N.I, M.T., B.B.) and Laboratory of Molecular Pharmaceutics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K.).
  • Kusuhara H; Pharmacokinetics and Non-Clinical Safety Department, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan (A.S., N.I, M.T., B.B.) and Laboratory of Molecular Pharmaceutics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (H.K.) kusuhara@mol.f.u-tokyo.ac.jp.
Drug Metab Dispos ; 49(2): 152-158, 2021 02.
Article em En | MEDLINE | ID: mdl-33262224
ABSTRACT
Multidrug and toxin extrusion (MATE) transporters are expressed on the luminal membrane of renal proximal tubule cells and extrude their substrates into the luminal side of the tubules. Inhibition of MATE1 can reduce renal secretory clearance of its substrate drugs and lead to drug-drug interactions (DDIs). To address whether IC50 values of MATE1 inhibitors with regard to their extracellular concentrations are affected by the direction of MATE1-mediated transport, we established an efflux assay of 1-methyl-4-phenylpyridinium (MPP+) and metformin using the human embryonic kidney 293 model transiently expressing human MATE1. The efflux rate was defined by reduction of the cellular amount of MPP+ and metformin for 0.25 minutes shortly after the removal of extracellular MPP+ and metformin. Inhibition potencies of 12 inhibitors toward MATE1-mediated transport were determined in both uptake and efflux assays. When MPP+ was used as a substrate, 8 out of 12 inhibitors showed comparable IC50 values between assays (<4-fold). IC50 values from the efflux assays were higher for cimetidine (9.9-fold), trimethoprim (10-fold), famotidine (6.4-fold), and cephalexin (>3.8-fold). When metformin was used as a substrate, IC50 values of the tested inhibitors when evaluated using uptake and efflux assays were within 4-fold of each other, with the exception of cephalexin (>4.7-fold). IC50 values obtained from the uptake assay using metformin showed smaller IC50 values than those from the efflux assay. Therefore, the uptake assay is recommended to determine IC50 values for the DDI predictions. SIGNIFICANCE STATEMENT In this study, a new method to evaluate IC50 values of extracellular added inhibitors utilizing an efflux assay was established. IC50 values were not largely different between uptake and efflux directions but were smaller for uptake. This study supports the rationale for a commonly accepted uptake assay with metformin as an in vitro probe substrate for multidrug and toxin extrusion 1-mediated drug-drug interaction risk assessment in drug development.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Preparações Farmacêuticas / 1-Metil-4-fenilpiridínio / Proteínas de Transporte de Cátions Orgânicos / Metformina Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Preparações Farmacêuticas / 1-Metil-4-fenilpiridínio / Proteínas de Transporte de Cátions Orgânicos / Metformina Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article