Abstract
Rosuvastatin is a potent inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase and has been shown to be highly effective in reducing low-density lipoprotein cholesterol. Clinical trials have demonstrated that renal excretion and, in particular, tubular secretion, plays a role in rosuvastatin clearance. The aim of this study was to determine the involvement of the basolateral organic anion transporters, OAT1 and OAT3, in the renal uptake of rosuvastatin. Expression of human (h) OAT3 in Xenopus oocytes significantly increased the uptake of rosuvastatin above control levels (Km = 7.4 μM). In contrast hOAT1 did not mediate rosuvastatin uptake. Furthermore, hOAT3-mediated estrone-3-sulfate uptake could be inhibited, with a rank order of potency, by atorvastatin, rosuvastatin, simvastatin, and pravastatin, whereas hOAT1-mediated PAH uptake was only significantly inhibited by simvastatin. To estimate the contribution of hOAT3 to the overall renal uptake of rosuvastatin, a series of experiments were conducted using rat kidney slices. Rosuvastatin uptake in rat renal slices was abolished in the presence of the rat (r) Oat3-specific inhibitor benzylpenicillin, suggesting that rOat3 is responsible for the majority of rosuvastatin uptake across the basolateral membrane in rat kidney. From these findings, we can suggest that hOAT3 contributes to the renal uptake of rosuvastatin in humans.
Footnotes
-
This work was funded by AstraZeneca Pharmaceuticals LP. This work was presented in part in Windass AS, Wang Y, and Brown CDA (2004). The role of hOAT1 and hOAT3 in the renal uptake of rosuvastatin, in AAPS Annual Meeting Abstract; 2004 Nov 7–11; Baltimore, MD. American Academy of Pharmaceutical Sciences, Arlington, VA.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.107.125831.
-
ABBREVIATIONS: OAT/Oat, organic anion transporter; h, human; r, rat; PAH, para-aminohippurate.
- Received May 16, 2007.
- Accepted June 20, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|