QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.049197v1 306/1/51    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kikuchi, R. Articles by Sugiyama, Y. Search for Related Content PubMed PubMed Citation Articles by Kikuchi, R. Articles by Sugiyama, Y. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB CIMETIDINE P-AMINOHIPPURIC ACID PENICILLIN G TRITIUM

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Contribution of Organic Anion Transporter 3 (Slc22a8) to the Elimination of p-Aminohippuric Acid and Benzylpenicillin across the Blood-Brain Barrier

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

The role of rat organic anion transporter 3 (rOat3; Slc22a8) in the efflux transport at the blood-brain barrier (BBB) was characterized. The expression of rOat1, rOat2, and rOat3 in the brain capillary endothelial cells (BCEC) was examined using reverse transcription-polymerase chain reaction analysis, which showed that there was no expression of rOat1 or rOat2, but moderate expression of rOat3. The expression of rOat3 in the BCEC was further confirmed by Western blotting. Immunohistochemical staining showed that rOat3 is located on the abluminal and, possibly, luminal membrane of the BCEC. The contribution of rOat3 to the efflux of para-aminohippuric acid (PAH) and benzylpenicillin (PCG), substrates of rOat3, from the cerebrum into the blood circulation across the BBB was evaluated using the Brain Efflux Index method. PAH and PCG were eliminated from the cerebrum with rate constants of 0.039 and 0.043 min^–1, respectively, and the elimination was saturated at high substrate concentrations. Taking account of the dilution in the brain, the K_m values for the elimination of PAH and PCG were estimated to be 168 and 29 µM, respectively. The efflux of PAH and PCG across the BBB was inhibited in a dose-dependent manner by unlabeled PCG and PAH, respectively. The K_i value of PAH for the efflux of PCG was 106 µM and that of PCG for the efflux of PAH was 58 µM. These values were comparable with their K_m values, suggesting that they share the same efflux mechanism at the BBB. Furthermore, cimetidine and pravastatin, which are also substrates and inhibitors of rOat3, significantly inhibited the efflux of PAH and PCG from the cerebrum. These results suggest that rOat3 is responsible for the elimination of PAH and PCG from the brain across the BBB.

Address correspondence to: Yuichi Sugiyama, Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: sugiyama{at}mol.f.utokyo.ac.jp

This article has been cited by other articles:

				K.-i. Hosoya, A. Makihara, Y. Tsujikawa, D. Yoneyama, S. Mori, T. Terasaki, S.-i. Akanuma, M. Tomi, and M. Tachikawa Roles of Inner Blood-Retinal Barrier Organic Anion Transporter 3 in the Vitreous/Retina-to-Blood Efflux Transport of p-Aminohippuric Acid, Benzylpenicillin, and 6-Mercaptopurine J. Pharmacol. Exp. Ther., April 1, 2009; 329(1): 87 - 93. [Abstract] [Full Text] [PDF]

				A. Ose, M. Ito, H. Kusuhara, K. Yamatsugu, M. Kanai, M. Shibasaki, M. Hosokawa, J. D. Schuetz, and Y. Sugiyama Limited Brain Distribution of [3R,4R,5S]-4-Acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (Ro 64-0802), a Pharmacologically Active Form of Oseltamivir, by Active Efflux across the Blood-Brain Barrier Mediated by Organic Anion Transporter 3 (Oat3/Slc22a8) and Multidrug Resistance-Associated Protein 4 (Mrp4/Abcc4) Drug Metab. Dispos., February 1, 2009; 37(2): 315 - 321. [Abstract] [Full Text] [PDF]

				S. S. Jhee, M. Yen, L. Ereshefsky, M. Leibowitz, M. Schulte, B. Kaeser, L. Boak, A. Patel, G. Hoffmann, E. P. Prinssen, et al. Low Penetration of Oseltamivir and Its Carboxylate into Cerebrospinal Fluid in Healthy Japanese and Caucasian Volunteers Antimicrob. Agents Chemother., October 1, 2008; 52(10): 3687 - 3693. [Abstract] [Full Text] [PDF]

				A. Ose, H. Kusuhara, K. Yamatsugu, M. Kanai, M. Shibasaki, T. Fujita, A. Yamamoto, and Y. Sugiyama P-glycoprotein Restricts the Penetration of Oseltamivir Across the Blood-Brain Barrier Drug Metab. Dispos., February 1, 2008; 36(2): 427 - 434. [Abstract] [Full Text] [PDF]

				R. Kikuchi, H. Kusuhara, N. Hattori, K. Shiota, I. Kim, F. J. Gonzalez, and Y. Sugiyama Regulation of the Expression of Human Organic Anion Transporter 3 by Hepatocyte Nuclear Factor 1{alpha}/beta and DNA Methylation Mol. Pharmacol., September 1, 2006; 70(3): 887 - 896. [Abstract] [Full Text] [PDF]

				R. K. Bhardwaj, D. Herrera-Ruiz, P. J. Sinko, O. S. Gudmundsson, and G. Knipp Delineation of Human Peptide Transporter 1 (hPepT1)-Mediated Uptake and Transport of Substrates with Varying Transporter Affinities Utilizing Stably Transfected hPepT1/Madin-Darby Canine Kidney Clones and Caco-2 Cells J. Pharmacol. Exp. Ther., September 1, 2005; 314(3): 1093 - 1100. [Abstract] [Full Text] [PDF]

				M. Kuroda, H. Kusuhara, H. Endou, and Y. Sugiyama Rapid Elimination of Cefaclor from the Cerebrospinal Fluid Is Mediated by a Benzylpenicillin-Sensitive Mechanism Distinct from Organic Anion Transporter 3 J. Pharmacol. Exp. Ther., August 1, 2005; 314(2): 855 - 861. [Abstract] [Full Text] [PDF]

				R. Kikuchi, H. Kusuhara, T. Abe, H. Endou, and Y. Sugiyama Involvement of Multiple Transporters in the Efflux of 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors across the Blood-Brain Barrier J. Pharmacol. Exp. Ther., December 1, 2004; 311(3): 1147 - 1153. [Abstract] [Full Text] [PDF]