| Title | Functional characterization of mouse Oatp1a4 in the uptake and efflux of drugs across the blood-brain barrier. | | Author(s) | Ose A, Kusuhara H, Endo C, Tohyama K, Miyajima M, Kitamura S, Sugiyama Y | | Institution | The University of Tokyo. | | Source | Drug Metab Dispos 2009 Oct 15. | | 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 HEK293 cells expressing mouse Oatp1a4 identified the following compounds as Oatp1a4 substrates: pitavastatin (K(m) 8.3 muM), rosuvastatin (K(m) 12 muM), pravastatin, taurocholate (K(m) 40 muM), 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 following microinjection into the cerebral cortex were significantly decreased in Oatp1a4(-/-) mice compared with 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 compared with wild-type mice, while that of pravastatin and [D-penicillamine(2,5)]-enkephalin was unchanged. The blood-to-brain transport of digoxin was significantly lower in Oatp1a4(-/-) mice compared with wild-type mice only when P-gp was inhibited by GF120918. Taken together, 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19833843 |
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