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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on August 3, 2004; DOI: 10.1124/jpet.104.071621

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Received for publication May 24, 2004.
Revised July 5, 2004.
Accepted for publication August 3, 2004.

Involvement of multiple transporters in the efflux of HMG-CoA reductase inhibitors across the blood-brain barrier

Ryota Kikuchi 1, Hiroyuki Kusuhara 1, Takaaki Abe 2, Hitoshi Endou 3, Yuichi Sugiyama 1*

1 The University of Tokyo 2 Tohoku University School of Medicine 3 Kyorin University School of Medicine

* Address correspondence to: E-mail: sugiyama{at}mol.f.u-tokyo.ac.jp

Abstract

Statins, HMG-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 vs 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.


Key words: HMG-CoA reductase inhibitor, Oat, Oatp, blood-brain barrier, efflux, organic anion transporter


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