Received for publication April 2, 2008.
Revised July 3, 2008.
Accepted for publication July 7, 2008.

Human proximal tubular epithelium actively secretes but does not retain rosuvastatin

Abstract

Rosuvastatin is a potent HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoenzymA) reductase inhibitor that has proven to be effective in the treatment of dyslipidemia. Rosuvastatin is cleared from the body both by biliary and renal clearance, the latter thought to be due to active tubular secretion. Whereas the mechanisms of hepatic clearance of rosuvastatin are well documented, those of renal clearance are not. Because rosuvastatin (and other statins) may alter proximal tubular function, this study aimed to characterise the mechanisms of tubular rosuvastatin secretion in order to define the factors that could influence the presence/concentration of rosuvastatin in proximal tubular cells. Hereto polarised monolayers of primary human tubular cells were used. We found rosuvastatin net secretion across proximal tubule cells, which was saturable (K₅₀=20.4±4.1µM). The basolateral uptake step was rate limiting, and mediated by OAT3 (organic aniontransporter-3). Rosuvastatin efflux at the apical membrane was mediated by MRP2/4 (Multidrug resistance associated protein-2/4) and ABCG2 (ATP binding cassette-G2) together with a small contribution from MDR1 (Multidrug resistance-1 or P-glycoprotein). These data, obtained in an intact human tubule cell model, provide a detailed insight into rosuvastatins renal handling and the possible factors influencing it.

Key words: MDR/p-Glycoprotein, Organic anion