J Pharm Sci 2004 Feb 01;932:262-72. doi: 10.1002/jps.10534.

Transporter-mediated renal handling of nafamostat mesilate.

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Nafamostat mesilate (NM) is a serine-protease inhibitor that is rapidly eliminated from the circulation and accumulated in the kidney. This study was conducted to characterize the mechanism of NM transport in the kidney because a serious side effect of NM-induced hyperkalemia may be related to accumulation of NM in the kidney. Measurements of uptake of NM in vivo by the kidney uptake index (KUI) method and of transport in an in vitro-cultured LLC-PK1 cell system suggested the involvement of an organic cation transporter (OCT). To clarify the involvement of OCTs located in the basolateral membrane of proximal tubules, we evaluated NM transport by OCTs expressed in Xenopus laevis oocytes. The IC(50) values of NM on [(14)C]TEA ([(14)C]tetraethylammonium) uptake by rOCT1, rOCT2, and hOCT2 were 50, 0.5, and 20 microM, respectively, and NM was concluded to be a substrate of OCTs. To investigate the transport of NM across the brush-border membrane, we examined the uptake of NM into brush-border membrane vesicles (BBMVs) isolated from rat renal cortex. NM was taken up into the BBMVs, and the uptake was decreased by unlabeled NM and temperature, implying that a transporter(s) is also involved in NM transport across the apical membrane. NM was not a substrate of hOCTN1, hOCTN2, or P-gp, implying the involvement of some unknown transporter(s). Thus, renal accumulation of NM can be explained by the involvement of the basolateral OCTs, though the influence of the apical membrane transporter remains to be clarified.

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Species referenced: Xenopus laevis
Genes referenced: pklr