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 ofp-aminohippurate (PAH) and pravastatin, respectively, with the Michaelis-Menten constants (K_mvalues) of 60 μM for rOat1-meditad PAH uptake and 13 μM for rOat3-mediated pravastatin uptake. Saturable uptake of PAH and pravastatin was observed in kidney slices withK_m values of 69 and 11 μM, 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.