Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the Hepatic Uptake of Pitavastatin in Humans (original) (raw)
Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION
Journal of Pharmacology and Experimental Therapeutics October 2004, 311 (1) 139-146; DOI: https://doi.org/10.1124/jpet.104.068056
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 _K_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.
Footnotes
This study was supported by Health and Labor Sciences Research grants from the Ministry of Health, Labor, and Welfare for the Research on Advanced Medical Technology and by Grant-in Aid for Young Scientists B 15790087 from the Ministry of Education, Culture, Sports, Science, and Technology.
doi:10.1124/jpet.104.068056.
ABBREVIATIONS: HMG, 3-hydroxy-3-methylglutaryl; OATP, organic anion transporting polypeptide; E217βG, estradiol 17β-d-glucuronide; E-sul, estrone-3-sulfate; CCK-8, cholecystokinin octapeptide; PCR, polymerase chain reaction; TBS-T, Tris-buffered saline containing 0.05% Tween 20; RAF, relative activity factor; CL, clearance.
- Received March 8, 2004.
- Accepted May 24, 2004.
The American Society for Pharmacology and Experimental Therapeutics
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