Functional Involvement of Rat Organic Anion Transporter 3 (rOat3;Slc22a8) in the Renal Uptake of Organic Anions

Abstract

Our previous kinetic analyses have shown that the transporter responsible for the renal uptake of pravastatin, an HMG-CoA reductase inhibitor, differs from that involved in its hepatic uptake. Although organic anion transporting polypeptides are now known to be responsible for the hepatic uptake of pravastatin, the renal uptake mechanism has not been clarified yet. In the present study, the involvement of rat organic anion transporter 3 (rOat3; Slc22a8) in the renal uptake of pravastatin was investigated. Immunohistochemical staining indicates the basolateral localization of rOat3 in the kidney. rOat1-and rOat3-expressed LLC-PK1 cells exhibited specific uptake of p-aminohippurate (PAH) and pravastatin, respectively, with the Michaelis-Menten constants (K m values) of 60 M for rOat1-meditad PAH uptake and 13 M for rOat3-mediated pravastatin uptake. Saturable uptake of PAH and pravastatin was observed in kidney slices with K m values of 69 and 11 M, respectively. The difference in the potency of PAH and pravastatin in inhibiting uptake by kidney slices suggests that different transporters are responsible for their renal uptake. This was also supported by the difference in the degree of inhibition by benzylpenicillin, a relatively selective inhibitor of rOat3, for the uptake of PAH and pravastatin by kidney slices. These results suggest that rOat1 and rOat3 are mainly responsible for the renal uptake of PAH and pravastatin, respectively.

Pharmacokinetic interaction between pravastatin and olmesartan in relation to SLCO1B1 polymorphism

“…The mechanism by which urinary excretion of olmesartan was reduced after the co-administration of pravastatin is unclear and still needs to be clarified. Recent in vitro studies indicated that organic anion transporter 3 (OAT3) expressed at the basolateral membrane of renal proximal tubule epithelial cells is predominantly involved in renal uptake of both pravastatin and olmesartan (Hasegawa et al 2002;Yamada et al 2007). The drug-drug interaction via OAT3 between pravastatin and olmesartan may account for the reduction of olmesartan renal excretion in the co-administration phase; however, the interaction via MRP2, which also is expressed in the kidney, cannot be ruled out (Kivistö et al 2005;Nakagomi-Hagihara et al 2006).…”

“…Pravastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase used for the treatment of hypercholesterolemia. Although pravastatin is not significantly metabolized by cytochrome P450 (CYP) isoenzymes, cumulative evidence has suggested that multiple membrane transporters are involved in the absorption (Kobayashi et al 2003), hepatobiliary excretion (Hirano et al 2005;Kivistö et al 2005;Nakai et al 2001), and renal excretion (Hasegawa et al 2002) of pravastatin. Organic anion transporting polypeptide (OATP) 1B1 (gene SLCO1B1) is an uptake transporter expressed at the sinusoidal membrane of hepatocytes, mediating the uptake of various endogenous and exogenous substances from the blood circulation into hepatocytes in a sodium-independent manner.…”

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

“…Western blotting was performed as described previously (8). ECL advance Western blotting Detection reagent (Amersham Pharmacia Biotech, Buckinghamshire, UK) was used for detection.…”

Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics

“…The classic basolateral OAT system, long referred to as the p-aminohippurate (PAH) transporter, was originally identified as novel kidney transporter (NKT) (24), which was proposed to function in renal organic ion secretion and was later directly shown to function in this capacity and named OAT1 (7,34). The other primary candidate for basolateral OA uptake is OAT3, originally identified as Roct [reduced in osteosclerosis (oc) transporter] (4), and several immunohistochemical studies have localized both OAT1 and OAT3 to the basolateral membrane of the proximal tubule of human, rat, and mouse (1,8,15,16,20,23,26,35). When expressed in Xenopus oocytes or epithelial cell lines, OAT1 couples OA entry to dicarboxylate exit and was trans-stimulated by preloading with PAH (34).…”