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Vol. 300, Issue 3, 746-753, March 2002
Graduate School of Pharmaceutical Sciences, University of Tokyo,
Hongo, Bunkyo-ku, Tokyo, Japan (M.H., H.K., D.S., Y.S.); Graduate
School of Pharmaceutical Sciences, Chiba University, Yayoi-chou,
Inage-ku, Chiba, Japan (K.I., S.U.); Department of Pharmacology and
Toxicology, Kyorin University School of Medicine, Shinkawa, Mitaka,
Tokyo, Japan (H. E.); and Core Research for Evolutional Science
and Technology, Japan Science and Technology Corporation, Tokyo, Japan
(H. K., Y. S.)
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 (Km
values) 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 with
Km 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.
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