Pravastatin, an HMG-CoA reductase inhibitor, is transported by rat organic anion transporting polypeptide, oatp2.
OBJECTIVE
We previously demonstrated the HMG-CoA reductase inhibitor, pravastatin, is actively taken up into isolated rat hepatocytes through multispecific organic anion transporters. The present study examined whether a newly cloned organic anion transporting polypeptide (oatp2) transports pravastatin.


METHODS
We investigated functional expression of oatp2 in Xenopus laevis oocytes, to examine [14C] pravastatin uptake.


RESULTS
[14C] Pravastatin (30 microM) uptake into oatp2 cRNA-injected oocytes was 40 times higher than that of water-injected control oocytes. The oatp2-mediated pravastatin uptake was Na+-independent and saturable. The Michaelis-Menten constant was 37.5+/-9.9 microM, a level comparable to that obtained in isolated rat hepatocytes in our previous study. As is the case with rat hepatocytes, the uptake of pravastatin (30 microM) was inhibited by 300 microM concentrations of taurocholate, cholate, bromosulfophthalein, estradiol-17beta-glucuronide, and simvastatin acid, but not by para-aminohippurate. On the other hand, [14C] simvastatin acid (30 microM) uptake of oatp2 cRNA-injected oocytes was not significantly different from that of water-injected oocytes.


CONCLUSIONS
The cloned oatp2 was identified as the transporter responsible for the active hepatocellular pravastatin uptake.
Tokui
T
T
Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Nakai
D
D
Nakagomi
R
R
Yawo
H
H
Abe
T
T
Sugiyama
Y
Y
D000818:Animals; D027321:Anion Transport Proteins; D001692:Biological Transport; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000378:metabolism*; D020355:Cholates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D009865:Oocytes / Q000378:metabolism; D017035:Pravastatin / Q000493:pharmacokinetics*; D051381:Rats; D019821:Simvastatin / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D014982:Xenopus laevis
D027321:Anion Transport Proteins; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D020355:Cholates; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C063287:simvastatin acid; D019821:Simvastatin; D017035:Pravastatin