TY - JOUR T1 - Involvement of Intestinal Uptake Transporters in the Absorption of Azithromycin and Clarithromycin in the Rat JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2492 LP - 2498 DO - 10.1124/dmd.108.022285 VL - 36 IS - 12 AU - Eric Garver AU - Erin D. Hugger AU - Shawn P. Shearn AU - Anuradha Rao AU - Paul A. Dawson AU - Charles B. Davis AU - Chao Han Y1 - 2008/12/01 UR - http://dmd.aspetjournals.org/content/36/12/2492.abstract N2 - Macrolide antibiotics azithromycin (AZI) and clarithromycin (CLARI) are large molecular weight compounds and are substrates for apically polarized efflux transporters such as P-glycoprotein, which can potentially restrict intestinal absorption. However, despite these undesired physicochemical and biopharmaceutical properties, AZI and CLARI exhibit moderate to excellent p.o. bioavailability in preclinical species and humans. Intestinal uptake transporters, such as organic anion transporting polypeptides (OATPs), can facilitate the uptake of drugs that are substrates and hence increase p.o. absorption. The present study was designed to determine whether the intestinal Oatps are involved in absorption of these macrolides. AZI or CLARI was dosed p.o. to Sprague-Dawley rats after p.o. administration with vehicle or rifamycin SV (RIF), an OATP inhibitor. The p.o. exposures of AZI and CLARI were reduced 65 and 45%, respectively, when coadministered with an optimized RIF regimen. The p.o. RIF had no affect on the total blood clearance of these macrolides and most likely did not cause induction of metabolizing enzymes and/or transporters. Therefore, the results suggest that inhibition of an RIF-sensitive uptake transporter such as Oatp along the rat gastrointestinal tract was responsible for reduced p.o. exposure of AZI and CLARI. In addition, AZI and CLARI caused inhibition of taurocholate uptake in rat Oatp1a5-transfected Madin-Darby canine kidney cell monolayers. The in vitro and in vivo results suggest that the intestinal Oatps are involved in the p.o. absorption of AZI and CLARI in the rat. The American Society for Pharmacology and Experimental Therapeutics ER -