Impact of Experimental Conditions on the Evaluation of Interactions between Multidrug and Toxin Extrusion Proteins and Candidate Drugs

• Published in: Drug metabolism and disposition 2016-08, Vol.44 (8), p.1381-1389
• Main Authors: Lechner, Christian, Ishiguro, Naoki, Fukuhara, Ayano, Shimizu, Hidetada, Ohtsu, Naoko, Takatani, Masahito, Nishiyama, Kotaro, Washio, Ikumi, Yamamura, Norio, Kusuhara, Hiroyuki
• Format: Article
• Language: English
• Subjects: 1-Methyl-4-phenylpyridinium - metabolism; Biological Transport; Buffers; Dose-Response Relationship, Drug; Drug Interactions; Estrone - analogs & derivatives; Estrone - metabolism; HEK293 Cells; Humans; Hydrogen-Ion Concentration; Kinetics; Membrane Transport Modulators - pharmacology; Metformin - metabolism; Organic Cation Transport Proteins - antagonists & inhibitors; Organic Cation Transport Proteins - genetics; Organic Cation Transport Proteins - metabolism; Rhodamine 123 - metabolism; Risk Assessment; Thiamine - metabolism; Transfection
• ISSN: 1521-009X; 0090-9556; 1521-009X
• DOI: 10.1124/dmd.115.068163

Multidrug and toxin extrusion transporters (MATEs) have a determining influence on the pharmacokinetic profiles of many drugs and are involved in several clinical drug-drug interactions (DDIs). Cellular uptake assays with recombinant cells expressing human MATE1 or MATE2-K are widely used to investigate MATE-mediated transport for DDI assessment; however, the experimental conditions and used test substrates vary among laboratories. We therefore initially examined the impact of three assay conditions that have been applied for MATE substrate and inhibitor profiling in the literature. One of the tested conditions resulted in significantly higher uptake rates of the three test substrates, [(14)C]metformin, [(3)H]thiamine, and [(3)H]1-methyl-4-phenylpyridinium (MPP(+)), but IC50 values of four tested MATE inhibitors varied only slightly among the three conditions (