Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the Hepatic Uptake of Pitavastatin in Humans

TLDR

Pitavastatin is a potent HMG‑CoA reductase inhibitor that accumulates selectively in the liver of rats, yet its hepatic uptake mechanism has not been clarified. The study aimed to quantify the contributions of OATP2/OATP1B1 and OATP8/OATP1B3 to pitavastatin hepatic uptake using transporter‑expressing cells and human cryopreserved hepatocytes, and to determine which transporter is most important. Researchers employed HEK293 cells expressing OATP2 or OATP8 and human cryopreserved hepatocytes, applying a relative activity factor–like method that compared pitavastatin uptake clearance to that of selective reference substrates to estimate each transporter’s quantitative contribution. Pitavastatin uptake was saturable and Na⁺‑independent with Km values of 3.0 and 3.3 µM for OATP2 and OATP8, respectively; in human hepatocytes the clearance was almost entirely mediated by these transporters, with OATP2 accounting for ~90 % of total hepatic clearance, confirming it as the primary transporter.

Abstract

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 <i>K</i>_m values of 3.0 and 3.3 μM 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.