Involvement of multiple transporters in the efflux of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors across the blood-brain barrier.
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 microl/min/g brain). The efflux of pravastatin and pitavastatin was saturable (apparent Km values: 18 and 5 muM, 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.
Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Ryota
R
Kikuchi
Hiroyuki
H
Kusuhara
Takaaki
T
Abe
Hitoshi
H
Endou
Yuichi
Y
Sugiyama
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain; D002352:Carrier Proteins / Q000378:metabolism*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004077:Digoxin / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008845:Microinjections; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D017035:Pravastatin / Q000493:pharmacokinetics; D011804:Quinolines / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D013656:Taurocholic Acid / Q000378:metabolism; D010130:p-Aminohippuric Acid / Q000378:metabolism
D002352:Carrier Proteins; D018076:DNA, Complementary; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D029362:Organic Anion Transporters, Sodium-Independent; D011804:Quinolines; D011994:Recombinant Proteins; C088800:Slc22a7 protein, rat; C114338:organic anion transport protein 3; D013656:Taurocholic Acid; D004077:Digoxin; D017035:Pravastatin; C108475:pitavastatin; D010130:p-Aminohippuric Acid