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

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.107.018903v1 36/4/796    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 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 Ishiguro, N. Articles by Sugiyama, Y. Search for Related Content PubMed PubMed Citation Articles by Ishiguro, N. Articles by Sugiyama, Y.

Establishment of a Set of Double Transfectants Coexpressing Organic Anion Transporting Polypeptide 1B3 and Hepatic Efflux Transporters for the Characterization of the Hepatobiliary Transport of Telmisartan Acylglucuronide

Department of Pharmacokinetics and Non-Clinical Safety, Kawanishi Pharma Research Institute, Nippon Boehringer Ingelheim Co., Yato, Kawanishi, Hyogo, Japan (N.I., A.S., W.K., T.I.); Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan (K.M., S.M., Y.S.); and Department of Pharmacokinetics and Drug Metabolism, Boehringer Ingelheim Pharma KG, Biberach on der Riss, Germany (T.E., W.R.)

In the hepatic uptake of organic anions, organic anion transporting polypeptide (OATP) 1B1 is believed to be mainly involved. We have constructed a set of double-transfected cells coexpressing OATP1B1 and hepatic efflux transporters and characterized the transcellular transport of several anions. Recent reports have also suggested the importance of OATP1B3 in the hepatic uptake of some compounds. However, there is little information about OATP1B3-selective substrate and no good tool for the evaluation of efflux transporters of OATP1B3 substrates. In the present study, we found an OATP1B3-selective substrate and established a novel set of double transfectants expressing OATP1B3. Telmisartan acylglucuronide (tel-glu) is a main metabolite of telmisartan, an angiotensin II receptor antagonist. Tel-glu is recognized by hepatobiliary transport systems and efficiently distributed to liver. Several studies using rat and human hepatocytes and transporter-expressing cells revealed that OATP1B3 was responsible for the hepatic uptake of tel-glu in humans. By using double transfectants expressing OATP1B3, we investigated the transcellular transport of tel-glu as well as estradiol 17β-D-glucuronide (E₂17βG) and cholecystokinin octapeptide (CCK-8) to identify the responsible efflux transporters in their biliary excretion. Vectorial basal-to-apical transport of tel-glu was observed in all kinds of double transfectants expressing OATP1B3. In contrast, basal-to-apical transport of E₂17βG and CCK-8 was seen only in the OATP1B3/MRP2 double transfectant compared with OATP1B3-expressing cells. Therefore, the newly established set of double transfectants expressing OATP1B3 combined with OATP1B1-expressing double transfectants can be used as a powerful tool for the rapid identification of hepatic uptake and efflux transporters of organic anions.

This article has been cited by other articles:

				R. Evers and X.-Y. Chu Role of the Murine Organic Anion-Transporting Polypeptide 1b2 (Oatp1b2) in Drug Disposition and Hepatotoxicity Mol. Pharmacol., August 1, 2008; 74(2): 309 - 311. [Abstract] [Full Text] [PDF]

				S. Matsushima, K. Maeda, H. Hayashi, Y. Debori, A. H. Schinkel, J. D. Schuetz, H. Kusuhara, and Y. Sugiyama Involvement of Multiple Efflux Transporters in Hepatic Disposition of Fexofenadine Mol. Pharmacol., May 1, 2008; 73(5): 1474 - 1483. [Abstract] [Full Text] [PDF]