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Pitavastatin, a novel potent 3-hydroxymethylglutaryl-CoA reductase inhibitor, is selectively distributed to the liver in rats. However, the hepatic uptake mechanism of pitavastatin has not been clarified yet. In the present study, we investigated the contribution of organic anion transporting polypeptide 2 (OATP2/OATP1B1) and OATP8 (OATP1B3) to pitavastatin uptake using transporter-expressing HEK293 cells and human cryopreserved hepatocytes. Uptake studies using OATP2- and OATP8-expressing cells revealed a saturable and Na(+)-independent uptake, with K(m) values of 3.0 and 3.3 microM for OATP2 and OATP8, respectively. To determine which transporter is more important for its hepatic uptake, we proposed a methodology for estimating their quantitative contribution to the overall hepatic uptake by comparing the uptake clearance of pitavastatin with that of reference compounds (a selective substrate for OATP2 (estrone-3-sulfate) and OATP8 (cholecystokinin octapeptide) in expression systems and human hepatocytes. The concept of this method is similar to the so-called relative activity factor method often used in estimating the contribution of each cytochrome P450 isoform to the overall metabolism. Applying this method to pitavastatin, the observed uptake clearance in human hepatocytes could be almost completely accounted for by OATP2 and OATP8, and about 90% of the total hepatic clearance could be accounted for by OATP2. This result was also supported by estimating the relative expression level of each transporter in expression systems and hepatocytes by Western blot analysis. These results suggest that OATP2 is the most important transporter for the hepatic uptake of pitavastatin in humans.

Agonists and antagonists selective for the brain-type [cholecystokinin (CCK)-B] and the peripheral-type (CCK-A) CCK receptor were used to localize the site(s) of action at which CCK inhibits food consumption. BC 264, a highly selective CCK-B receptor agonist, did not decrease consumption of a palatable meal when administered either i.p. or into the lateral ventricles of the brain, whereas CCK decreased feeding when administered i.p. at the same doses. CCK decreased feeding when administered i.v.t. at a high dose, 5 micrograms. L-364,718, an antagonist selective for the CCK-A receptor, blocked completely the action of centrally administered CCK, whereas L-365,260, a selective CCK-B receptor antagonist, had no effect on the ability of centrally administered CCK to inhibit feeding. To estimate the quantity of i.v.t. administered CCK which reached the periphery, a tracer of radiolabeled [3H]p-CCK8 ([3H]CCK octapeptide sulfate), combined with unlabeled pCCK8 (5 micrograms) was administered i.c.t. Thirty minutes after administration, intact radiolabeled pCCK8 was extracted from the plasma and measured in the blood in nanomolar concentrations, exceeding the amounts of CCK octapeptide sulfate reported previously to be present in the plasma after a meal. Intraventricularly administered CCK thus appears to reduce feeding in the rat through a mechanism involving a CCK-A receptor subtype in the periphery.