digoxin and pitavastatin

Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Digoxin; Drug Interactions; Drug Therapy, Combination; Humans; Phenytoin; Quinolines; Theophylline; Warfarin

This study investigated the role of a multispecific organic anion transporter, Oatp1a4/Slco1a4, in drug transport across the blood-brain barrier. In vitro transport studies using human embryonic kidney 293 cells expressing mouse Oatp1a4 identified the following compounds as Oatp1a4 substrates: pitavastatin (K(m) = 8.3 microM), rosuvastatin (K(m) = 12 microM), pravastatin, taurocholate (K(m) = 40 microM), digoxin, ochratoxin A, and [d-penicillamine(2,5)]-enkephalin. Double immunohistochemical staining of Oatp1a4 with P-glycoprotein (P-gp) or glial fibrillary acidic protein demonstrated that Oatp1a4 signals colocalized with P-gp signals partly but not with glial fibrillary acidic protein, suggesting that Oatp1a4 is expressed in both the luminal and the abluminal membranes of mouse brain capillary endothelial cells. The brain-to-blood transport of pitavastatin, rosuvastatin, pravastatin, and taurocholate after microinjection into the cerebral cortex was significantly decreased in Oatp1a4(-/-) mice compared with that in wild-type mice. The blood-to-brain transport of pitavastatin, rosuvastatin, taurocholate, and ochratoxin A, determined by in situ brain perfusion, was significantly lower in Oatp1a4(-/-) mice than in wild-type mice, whereas transport of pravastatin and [D-penicillamine(2,5)]-enkephalin was unchanged. The blood-to-brain transport of digoxin was significantly lower in Oatp1a4(-/-) mice than in wild-type mice only when P-gp was inhibited by N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918). Taken together, these results show that Oatp1a4 can mediate the brain-to-blood and blood-to-brain transport of its substrate drugs across the blood-brain barrier. The brain-to-plasma ratio of taurocholate, pitavastatin, and rosuvastatin was close to the capillary volume in wild-type mice, and it was not affected by Oatp1a4 dysfunction. Whether Oatp1a4 can deliver drugs from the blood to the brain remains controversial.

Topics: Acridines; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Blood-Brain Barrier; Brain; Capillaries; Cell Line; Cell Membrane; Cerebral Cortex; Choroid Plexus; Digoxin; Enkephalin, D-Penicillamine (2,5)-; Fluorobenzenes; Gene Expression; Humans; Ion Pumps; Kinetics; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Ochratoxins; Organic Anion Transporters; Organic Cation Transport Proteins; Pharmaceutical Preparations; Pravastatin; Pyrimidines; Quinolines; Recombinant Proteins; Rosuvastatin Calcium; Sulfonamides; Taurocholic Acid; Tetrahydroisoquinolines; Transfection

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.

Topics: Animals; Blood-Brain Barrier; Brain; Carrier Proteins; Digoxin; DNA, Complementary; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro Techniques; Kinetics; Male; Microinjections; Organic Anion Transporters, Sodium-Independent; p-Aminohippuric Acid; Pravastatin; Quinolines; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Taurocholic Acid