Organic Anion Transporter 3 (Oat3/Slc22a8) Interacts with Carboxyfluoroquinolones, and Deletion Increases Systemic Exposure to Ciprofloxacin
Document Type
Article
Original Publication Date
2008
Journal/Book/Conference Title
Molecular Pharmacology
Volume
74
Issue
1
First Page
122
Last Page
131
DOI of Original Publication
10.1124/mol.107.042853
Date of Submission
October 2015
Abstract
Carboxyfluoroquinolones, such as ciprofloxacin, are employed for numerous infectious diseases. Renal secretion is a major determinant of their systemic and urinary concentration, but the specific transporters involved are virtually unknown. In vivo studies implicate the organic anion transporter (OAT) family as a pivotal component of carboxyfluoroquinolone renal secretion. Therefore, this study identified the specific renal basolateral OAT(s) involved, thereby highlighting potential sources of carboxyfluoroquinolone-drug interactions and variable efficacy. Two heterologous expression systems, Xenopus laevis oocytes and cell monolayers, were employed to determine the roles of murine and human renal basolateral mOat1/hOAT1 and mOat3/hOAT3. Ciprofloxacin was transported by mOat3 in both systems (Km, 70±6 μM), and demonstrated no interaction with mOat1 or hOAT1. Furthermore, ciprofloxacin, norfloxacin, ofloxacin, and gatifloxacin exhibited concentration-dependent inhibition of transport on mOat3 in cells, with inhibition constants of 198±39, 558±75, 745±165, and 941±232 μM, respectively. Ciprofloxacin and gatifloxacin also inhibited hOAT3. Subsequently, in vivo elimination of ciprofloxacin was assessed in wild-type and Oat3 null mice (Oat3(-/-)). Oat3(-/-) mice exhibited significantly elevated plasma levels of ciprofloxacin at clinically-relevant concentrations (P<0.05, males; P<0.01, females). Oat3(-/-) mice also demonstrated a reduced volume of distribution (27%, P<0.01, males; 14%, P<0.01, females) and increased area under the concentration-time curve (25%, P<0.05, males; 33%, P<0.01, females). Female Oat3(-/-) mice had a 35% (P<0.01) reduction in total clearance of ciprofloxacin relative to wild-type. Additionally, putative ciprofloxacin metabolites were significantly elevated in Oat3(-/-) mice. The present findings indicate that polymorphisms of, and drug interactions on, hOAT3 may influence carboxyfluoroquinolone efficacy, especially in urinary tract infections.
Is Part Of
VCU Pharmaceutics Publications
Comments
Published in final edited form as: Mol Pharmacol. 2008 Jul; 74(1): 122. Published online 2008 Apr 1. doi: 10.1124/mol.107.042853 PMCID: PMC2822873 NIHMSID: NIHMS87648 Douglas H. Sweet was at Medical University of South Carolina at the time of publication.