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Research ArticleArticle

DRUG-DRUG INTERACTION BETWEEN PITAVASTATIN AND VARIOUS DRUGS VIA OATP1B1

Masaru Hirano, Kazuya Maeda, Yoshihisa Shitara and Yuichi Sugiyama
Drug Metabolism and Disposition July 2006, 34 (7) 1229-1236; DOI: https://doi.org/10.1124/dmd.106.009290
Masaru Hirano
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Kazuya Maeda
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Yoshihisa Shitara
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Yuichi Sugiyama
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Abstract

It has already been demonstrated that pitavastatin, a novel potent HMG-coenzyme A reductase inhibitor, is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP) 1B1. Because OATP2B1 is also localized in the basolateral membrane of human liver, we took two approaches to further confirm the minor contribution of OATP2B1 to the hepatic uptake of pitavastatin. Western blot analysis revealed that the ratio of the band density of OATP2B1 in human hepatocytes to that in our expression system is at least 6-fold lower compared with OATP1B1 and OATP1B3. The uptake of pitavastatin in human hepatocytes could be inhibited by both estrone-3-sulfate (OATP1B1/OATP2B1 inhibitor) and estradiol-17β-d-glucuronide (OATP1B1/OATP1B3 inhibitor). These results further supported the idea that OATP1B1 is a predominant transporter for the hepatic uptake of pitavastatin. Then, to explore the possibility of OATP1B1-mediated drug-drug interaction, we checked the inhibitory effects of various drugs on the pitavastatin uptake in OATP1B1-expressing cells and evaluated whether the in vitro inhibition was clinically significant or not. As we previously reported, we used the methodology for estimating the maximum unbound concentration of inhibitors at the inlet to the liver (Iu,in,max). Judging from Iu,in,max and inhibition constant (Ki) for OATP1B1, several drugs (especially cyclosporin A, rifampicin, rifamycin SV, clarithromycin, and indinavir) have potentials for interacting with OATP1B1-mediated uptake of pitavastatin. The in vitro experiments could support the clinically observed drug-drug interaction between pitavastatin and cyclosporin A. These results suggest that we should pay attention to the concomitant use of some drugs with pitavastatin.

Footnotes

  • This work was supported by Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare for the Research on Advanced Medical Technology and a Grant-in Aid for Young Scientists (B) (15790087) from the Ministry of Education, Culture, Sports, Science and Technology.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.009290.

  • ABBREVIATIONS: HEK, human embryonic kidney; MDCK, Madin-Darby canine kidney; OATP, organic anion-transporting polypeptide; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; Km, Michaelis constant; Vmax, maximum transport velocity; Ki, inhibition constant; E217βG, estradiol 17β-d-glucuronide; E1S, estrone-3-sulfate; DDI, drug-drug interaction.

    • Received January 6, 2006.
    • Accepted March 29, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (7)
Drug Metabolism and Disposition
Vol. 34, Issue 7
1 Jul 2006
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Research ArticleArticle

DRUG-DRUG INTERACTION BETWEEN PITAVASTATIN AND VARIOUS DRUGS VIA OATP1B1

Masaru Hirano, Kazuya Maeda, Yoshihisa Shitara and Yuichi Sugiyama
Drug Metabolism and Disposition July 1, 2006, 34 (7) 1229-1236; DOI: https://doi.org/10.1124/dmd.106.009290

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Research ArticleArticle

DRUG-DRUG INTERACTION BETWEEN PITAVASTATIN AND VARIOUS DRUGS VIA OATP1B1

Masaru Hirano, Kazuya Maeda, Yoshihisa Shitara and Yuichi Sugiyama
Drug Metabolism and Disposition July 1, 2006, 34 (7) 1229-1236; DOI: https://doi.org/10.1124/dmd.106.009290
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