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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Involvement of Multiple Transporters in the Efflux of 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors across the Blood-Brain Barrier

Ryota Kikuchi, Hiroyuki Kusuhara, Takaaki Abe, Hitoshi Endou and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics December 2004, 311 (3) 1147-1153; DOI: https://doi.org/10.1124/jpet.104.071621
Ryota Kikuchi
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Hiroyuki Kusuhara
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Takaaki Abe
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Hitoshi Endou
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Yuichi Sugiyama
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Abstract

Statins, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, are frequently used for the treatment of hypercholesterolemia. The present study aimed to examine the involvement of organic anion transporters in the efflux transport of pravastatin and pitavastatin across the blood-brain barrier (BBB). Transport studies using cDNA-transfected cells revealed that these statins are substrates of multispecific organic anion transporters expressed at the BBB (rOat3:Slc22a8 and rOatp2:Slco1a4). The efflux of these statins across the BBB was characterized using the brain efflux index method. The efflux clearance of pitavastatin across the BBB, obtained from the elimination rate constant and the distribution volume in the brain, was greater than that of pravastatin (364 versus 59 μl/min/g brain). The efflux of pravastatin and pitavastatin was saturable (apparent Km values: 18 and 5 μM, respectively) and inhibited by probenecid but unaffected by tetraethylammonium. Furthermore, an inhibitor of the efflux pathway for hydrophilic organic anions across the BBB (p-aminohippurate), and inhibitors of the efflux pathway for amphipathic organic anions (taurocholate and digoxin) inhibited the efflux of both statins. The degree of inhibition by p-aminohippurate was similar and partial for the efflux of pravastatin and pitavastatin. Taurocholate and digoxin completely inhibited the efflux of pitavastatin, whereas their effect was partial for the efflux of pravastatin. The results of the present study suggest the involvement of multiple transporters, including rOat3 and rOatp2, in the efflux transport of pravastatin and pitavastatin across the BBB, each making a different contribution.

Footnotes

  • This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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

  • doi:10.1124/jpet.104.071621.

  • ABBREVIATIONS: Oat, organic anion transporter; Oatp, organic anion-transporting polypeptide; CNS, central nervous system; BBB, blood-brain barrier; HMG, 3-hydroxy-3-methylglutaryl; BEI, brain efflux index; PAH, p-aminohippurate; TCA, taurocholate.

    • Received May 18, 2004.
    • Accepted August 3, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 311 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 311, Issue 3
1 Dec 2004
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Involvement of Multiple Transporters in the Efflux of 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors across the Blood-Brain Barrier

Ryota Kikuchi, Hiroyuki Kusuhara, Takaaki Abe, Hitoshi Endou and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics December 1, 2004, 311 (3) 1147-1153; DOI: https://doi.org/10.1124/jpet.104.071621

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Involvement of Multiple Transporters in the Efflux of 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors across the Blood-Brain Barrier

Ryota Kikuchi, Hiroyuki Kusuhara, Takaaki Abe, Hitoshi Endou and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics December 1, 2004, 311 (3) 1147-1153; DOI: https://doi.org/10.1124/jpet.104.071621
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