PT - JOURNAL ARTICLE AU - Tian Lan AU - Anuradha Rao AU - Jamie Haywood AU - Charles B. Davis AU - Chao Han AU - Eric Garver AU - Paul A. Dawson TI - Interaction of Macrolide Antibiotics with Intestinally Expressed Human and Rat Organic Anion-Transporting Polypeptides AID - 10.1124/dmd.109.028522 DP - 2009 Dec 01 TA - Drug Metabolism and Disposition PG - 2375--2382 VI - 37 IP - 12 4099 - http://dmd.aspetjournals.org/content/37/12/2375.short 4100 - http://dmd.aspetjournals.org/content/37/12/2375.full SO - Drug Metab Dispos2009 Dec 01; 37 AB - The macrolide antibiotics azithromycin and clarithromycin are large molecular weight compounds that exhibit moderate to excellent oral bioavailability in preclinical species and humans. Previous concomitant dosing studies in rats using rifamycin SV, a general organic anion-transporting polypeptide (OATP) inhibitor, suggested that the high oral absorption of azithromycin and clarithromycin may be caused by facilitative uptake by intestinal Oatps. In this study, we used OATP/Oatp-expressing cells to investigate the interaction of macrolides with rat Oatp1a5, human OATP1A2, and human/rat OATP2B1/Oatp2b1. These experiments showed that azithromycin and clarithromycin were potent inhibitors of rat Oatp1a5-mediated taurocholate uptake with apparent inhibitor constant (Ki) values of 3.3 and 2.4 μM, respectively. The macrolides functioned as noncompetitive inhibitors but were not transport substrates for rat Oatp1a5, as assessed by direct uptake measurements of radiolabeled azithromycin and clarithromycin. cis-Inhibition and direct uptake studies further showed that azithromycin and clarithromycin were only very weak inhibitors and not substrates for human OATP1A2 and human/rat OATP2B1/Oatp2b1. In summary, these results indicate that the macrolides azithromycin and clarithromycin potently inhibit rat Oatp1a5 but do not significantly interact with OATP1A2 and OATP2B1/Oatp2b1. These intestinally expressed OATP/Oatp(s) are not responsible for the postulated facilitative uptake of azithromycin and clarithromycin, and alternative facilitative pathways must exist for their intestinal absorption.Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics