Targeted disruption of the multidrug and toxin extrusion 1 (mate1) gene in mice reduces renal secretion of metformin

Abstract

Multidrug and toxin extrusion 1 (MATE1/SLC47A1) is important for excretion of organic cations in the kidney and liver, where it is located on the luminal side. Although its functional and regulatory characteristics have been clarified, its pharmacokinetic roles in vivo have yet to be elucidated. In the present study, to clarify the relevance of MATE1 in vivo, targeted disruption of the murine Mate1 gene was carried out. The lack of Mate1 expression in the kidney and liver was confirmed by reverse transcription-polymerase chain reaction and Western blot analysis. The mRNA levels of other organic cation transporters such as Octs did not differ significantly between wild-type [Mate1(+/+)] and Mate1 knockout [Mate1(-/-)] mice. It is noteworthy that the Mate1(-/-) mice were viable and fertile. Pharmacokinetic characterization was carried out using metformin, a typical substrate of MATE1. After a single intravenous administration of metformin (5 mg/kg), a 2-fold increase in the area under the blood concentration-time curve for 60 min (AUC(0-60)) of metformin in Mate1(-/-) mice was observed. Urinary excretion of metformin for 60 min after the intravenous administration was significantly decreased in Mate1(-/-) mice compared with Mate1(+/+) mice. The renal clearance (CL(ren)) and renal secretory clearance (CL(sec)) of metformin in Mate1(-/-) mice were approximately 18 and 14% of those in Mate1(+/+) mice, respectively. This is the first report to demonstrate an essential role of MATE1 in systemic clearance of metformin.