Multidrug resistance-associated protein 4 is involved in the urinary excretion of hydrochlorothiazide and furosemide.

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Hasegawa M, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K, Sugiyama Y

Multidrug resistance-associated protein 4 is involved in the urinary excretion of hydrochlorothiazide and furosemide.

J Am Soc Nephrol. 2007 Jan;18(1):37-45. doi: 10.1681/ASN.2005090966. Epub 2006 Nov 29.

PubMed ID

17135398 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Drugs

Hydrochlorothiazide

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Hydrochlorothiazide	Multidrug resistance-associated protein 4	Protein	Humans	Unknown	Substrate	Details
Hydrochlorothiazide	Solute carrier family 22 member 8	Protein	Humans	Unknown	Substrate	Details