title: Interaction of macrolide antibiotics with intestinally expressed human and rat organic anion-transporting polypeptides.
abstract: 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 (K(i)) values of 3.3 and 2.4 microM, 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.
authors.affiliation: Department of Internal Medicine, Section on Gastroenterology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Lan
authors.forename: Anuradha
authors.initials: A
authors.lastname: Rao
authors.forename: Jamie
authors.initials: J
authors.lastname: Haywood
authors.forename: Charles B
authors.initials: CB
authors.lastname: Davis
authors.forename: Chao
authors.initials: C
authors.lastname: Han
authors.forename: Eric
authors.initials: E
authors.lastname: Garver
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dawson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology; D001692:Biological Transport; D019556:COS Cells; D002522:Chlorocebus aethiops; D017291:Clarithromycin / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004917:Erythromycin / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D007700:Kinetics; D018942:Macrolides / Q000378:metabolism / Q000494:pharmacology*; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors; D051381:Rats; D013656:Taurocholic Acid / Q000378:metabolism; D014162:Transfection
chemical_list: D000900:Anti-Bacterial Agents; D017963:Azithromycin; D017291:Clarithromycin; D004917:Erythromycin; D004970:Estrone; D018942:Macrolides; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D013656:Taurocholic Acid; C512988:SLCO1A2 protein, human; C450859:SLCO2B1 protein, human; C421143:Slco1a5 protein, rat; C533062:Slco2b1 protein, rat; C017296:estrone sulfate