Received for publication June 4, 2008.
Revised August 26, 2008.
Accepted for publication August 27, 2008.

Involvement of Intestinal Uptake transporters in the Absorption of Azithromycin and Clarithromycin in the Rat

Abstract

Macrolide antibiotics azithromycin (AZI) and clarithromycin (CLARI) are large molecular weight compounds and are substrates for apically polarized efflux transporters such as P-glycoprotein (P-gp) which can potentially restrict intestinal absorption. However, despite these undesired physicochemical and biopharmaceutical properties, AZI and CLARI exhibit moderate to excellent oral bioavailability in preclinical species and human. Intestinal uptake transporters, such as OATPs, can facilitate the uptake of drugs that are substrates and hence, increase oral absorption. The present study was designed to determine whether the intestinal Oatps are involved in absorption of these macrolides. AZI or CLARI were dosed orally to SD-rats after oral administration with vehicle or rifamycin SV (RIF), an OATP inhibitor. Oral exposures of AZI and CLARI were reduced 65% and 45%, respectively, when co-administered with an optimized RIF regimen. Oral RIF had no impact 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 a RIF sensitive uptake transporter such as Oatp along the rat gastrointestinal tract was responsible for reduced oral exposure of AZI and CLARI. In addition, AZI and CLARI caused inhibition of taurocholate uptake in rat Oatp1a5-transfected MDCK cell monolayers. The in vitro and in vivo results suggest that the intestinal Oatps are involved in the oral absorption of AZI and CLARI in the rat.

Key words: absorption, active transport, antibiotics, drug interactions, intestinal bioavailability, intestinal transport, organic anion transport, permeability, pharmacokinetics, transporters