Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 98, Issue 7, Pages 2529-2539Publisher
ELSEVIER SCIENCE INC
DOI: 10.1002/jps.21618
Keywords
absorption; active transport; transporters; membrane transporter; organic anion-transporting polypeptide transporters; P-glycoprotein; intestinal secretion/transport
Funding
- Ministry of Education, Science and Culture of Japan
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Gastrointestinal absorption of several beta-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 beta-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. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2529-2539, 2009
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