Involvement of influx and efflux transport systems in gastrointestinal absorption of celiprolol

• Kato, Yukio

• Miyazaki, Tatsuya

• Kano, Takashi

• Sugiura, Tomoko

• Kubo, Yoshiyuki

• Tsuji, Akira

Abstract

金沢大学医薬保健研究域薬学系

Gastrointestinal absorption of several β-blockers is inhibited by citrus juices, although molecular mechanism(s) lying on their small intestinal absorption has not yet been identified. Here, we attempted to demonstrate involvement of both influx and efflux transporters in vivo in gastrointestinal absorption of celiprolol in mice. Plasma concentration of celiprolol (3 mg/kg) after oral administration was mostly under the limit of quantification in wild mice, whereas that in mdr1a/b knockout (mdr1a/b(-/-)) mice was much more obvious, indicating P-glycoprotein-mediated efflux. Then, the oral absorption of celiprolol in mdr1a/b(-/-) mice was further examined to investigate influx transport mechanism with avoiding effect of P-glycoprotein. Coadministration of bromosulfophthalein (BSP), an inhibitor of various influx transporters including organic anion transporting polypeptide (OATP) reduced plasma celiprolol concentration. Inhibition by BSP of celiprolol uptake from apical membranes was confirmed in Ussing-type chamber of small intestinal tissues. Uptake of celiprolol by human small intestinal transporter OATP-A/1A2 was also confirmed in Xenopus Laevis oocytes. Interestingly, OATP-A/1A2 accepts various b-blockers including acebutolol, atenolol and sotalol, oral absorption of which is inhibited by coadministration of citrus juice or telithromycin in human. Taken together, these findings have suggested fundamental role of influx transport system(s) in oral absorption of celiprolol. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association.

Journal

• Journal of Pharmaceutical Sciences

  Journal of Pharmaceutical Sciences 98 (7), 2529-2539, 2009-07-01

  John Wiley & Sons / American Pharmacists Association

Keywords

• Absorption
• Active transport
• Intestinal secretion/transport
• Membrane transporter
• Organic anion-transporting polypeptide transporters
• P-glycoprotein
• Transporters

Details

• CRID: 1050001335954049920
• NII Article ID: 120001451016
• NII Book ID: AA00704450
• ISSN: 00223549
• Web Site: http://hdl.handle.net/2297/18708
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • CiNii Articles
  • KAKEN