PT  - JOURNAL ARTICLE
AU  - Ose, Atsushi
AU  - Kusuhara, Hiroyuki
AU  - Endo, Chihiro
AU  - Tohyama, Kimio
AU  - Miyajima, Mari
AU  - Kitamura, Satoshi
AU  - Sugiyama, Yuichi
TI  - Functional Characterization of Mouse Organic Anion Transporting Peptide 1a4 in the Uptake and Efflux of Drugs Across the Blood-Brain Barrier
AID  - 10.1124/dmd.109.029454
DP  - 2010 Jan 01
TA  - Drug Metabolism and Disposition
PG  - 168--176
VI  - 38
IP  - 1
4099  - http://dmd.aspetjournals.org/content/38/1/168.short
4100  - http://dmd.aspetjournals.org/content/38/1/168.full
SO  - Drug Metab Dispos2010 Jan 01; 38
AB  - 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 (Km = 8.3 μM), rosuvastatin (Km = 12 μM), pravastatin, taurocholate (Km = 40 μM), digoxin, ochratoxin A, and [d-penicillamine2,5]-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-penicillamine2,5]-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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics