title: Functional characterization of mouse organic anion transporting peptide 1a4 in the uptake and efflux of drugs across the blood-brain barrier.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ose
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Chihiro
authors.initials: C
authors.lastname: Endo
authors.forename: Kimio
authors.initials: K
authors.lastname: Tohyama
authors.forename: Mari
authors.initials: M
authors.lastname: Miyajima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kitamura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D002196:Capillaries / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002831:Choroid Plexus / Q000098:blood supply / Q000378:metabolism; D004077:Digoxin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D016623:Ion Pumps / Q000235:genetics; D007700:Kinetics; D008099:Liver / Q000098:blood supply / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009793:Ochratoxins / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D017035:Pravastatin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D011804:Quinolines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D013656:Taurocholic Acid / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014162:Transfection
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D005464:Fluorobenzenes; D016623:Ion Pumps; C464433:Oatp2 protein, mouse; D009793:Ochratoxins; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D004364:Pharmaceutical Preparations; D011743:Pyrimidines; D011804:Quinolines; D011994:Recombinant Proteins; D013449:Sulfonamides; D044005:Tetrahydroisoquinolines; C025589:ochratoxin A; D013656:Taurocholic Acid; D004077:Digoxin; D000068718:Rosuvastatin Calcium; D020881:Enkephalin, D-Penicillamine (2,5)-; D017035:Pravastatin; C108475:pitavastatin; C083501:Elacridar