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Multidrug Resistance–Associated Protein 4 Is Involved in the Urinary Excretion of Hydrochlorothiazide and Furosemide

Maki Hasegawa^*, Hiroyuki Kusuhara^*, Masashi Adachi, John D. Schuetz, Kenji Takeuchi^* and Yuichi Sugiyama^*

^* Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan; and Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee

Address correspondence to: Dr. Hiroyuki Kusuhara, Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. Phone: +81-3-5841-4774; Fax: +81-3-5841-4766; E-mail: kusuhara{at}mol.f.u-tokyo.ac.jp

Received for publication September 19, 2005. Accepted for publication October 10, 2006.

The role of ATP-binding cassette transporters in the urinary excretion of diuretics was investigated. Significant ATP-dependent uptake of hydrochlorothiazide (HCT) and furosemide was observed in membrane vesicles that expressed multidrug resistance–associated protein 4 (MRP4) and breast cancer resistance protein (BCRP). Unlike taurocholate uptake, S-methylglutathione had no effect on the ATP-dependent uptake of both compounds by MRP4. The functional importance of MRP4 and BCRP in the urinary excretion of HCT and furosemide was investigated using gene knockout mice. The renal clearance of HCT and furosemide was reduced significantly but not abolished in Mrp4 knockout mice compared with wild-type mice (9.0 ± 0.9 versus 15 ± 2 ml/min per kg for HCT and 1.9 ± 0.3 versus 2.7 ± 0.1 ml/min per kg for furosemide), and the amount of HCT that was associated with the kidney specimens was greater in Mrp4 knockout mice (21 ± 3 versus 13 ± 1 nmol/g kidney). In contrast, Bcrp makes only a negligible contribution because the urinary excretion was unchanged in Bcrp knockout mice. Our results suggest that Mrp4, together with other unknown transporters, accounts for the luminal efflux of HCT and furosemide from proximal tubular epithelial cells.

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