PT  - JOURNAL ARTICLE
AU  - Shingo Watanabe
AU  - Masahiro Tsuda
AU  - Tomohiro Terada
AU  - Toshiya Katsura
AU  - Ken-ichi Inui
TI  - Reduced Renal Clearance of a Zwitterionic Substrate Cephalexin in <em>Mate1</em>-Deficient Mice
AID  - 10.1124/jpet.110.169433
DP  - 2010 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 651--656
VI  - 334
IP  - 2
4099  - http://jpet.aspetjournals.org/content/334/2/651.short
4100  - http://jpet.aspetjournals.org/content/334/2/651.full
SO  - J Pharmacol Exp Ther2010 Aug 01; 334
AB  - Multidrug and toxin extrusion 1 (MATE1/solute carrier 47A1) mediates the transport of not only organic cations but also zwitterions such as cephalexin. However, the contribution of MATE1 to tubular secretion of cephalexin in vivo has not been elucidated. In the present study, we carried out transport experiments of cephalexin via MATE1 and performed pharmacokinetic analyses of cephalexin in Mate1 knockout [Mate1(−/−)] mice. Cephalexin uptake by human MATE1-expressing human embryonic kidney 293 cells exhibited saturable kinetics (Km = 5.9 ± 0.5 mM) and a bell-shaped pH profile with a maximum at pH 7.0. We confirmed that mouse MATE1 also transported cephalexin. After a single intravenous administration of cephalexin (5 mg/kg), Mate1(−/−) mice showed higher plasma concentrations of cephalexin than wild-type [Mate1(+/+)] mice. The urinary excretion of cephalexin for 60 min was significantly reduced, and the renal concentration was markedly increased in Mate1(−/−) mice compared with Mate1(+/+) mice. The renal clearance of cephalexin in Mate1(−/−) mice was approximately 60% of that in Mate1(+/+) mice and seemed to be near the creatinine clearance. In contrast, there were no significant differences between both mice in the pharmacokinetics of anionic cefazolin, which is not a substrate for MATE1. In this study, we demonstrated that MATE1 is responsible for renal tubular secretion of a zwitterionic substrate cephalexin in vivo.