Abstract
Carboxyfluoroquinolones, such as ciprofloxacin, are used for the treatment of 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 used to determine the roles of murine and human renal basolateral mOat1/hOAT1 and mOat3/hOAT3. Ciprofloxacin was transported by mOat3 in both systems (Km value, 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. Thereafter, 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, male mice; P < 0.01, female mice). Oat3(-/-) mice also demonstrated a reduced volume of distribution (27%, P < 0.01, male mice; 14%, P < 0.01, female mice) and increased area under the concentration-time curve (25%, P < 0.05, male mice; 33%, P < 0.01, female mice). Female Oat3(-/-) mice had a 35% (P < 0.01) reduction in total clearance of ciprofloxacin relative to wild type. In addition, 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.
Footnotes
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This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases grant R01-DK067216 (to D.H.S.), by fellowship provisions from the American Foundation for Pharmaceutical Education (to A.L.V.), and by the National Institutes of Health grant C0-RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources.
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ABBREVIATIONS: LLC-PK1, porcine kidney cells; AUC, area under the concentration-time curve; CHO, Chinese hamster ovary cells; CHO-FRT, empty vector-transfected Chinese hamster ovary; CHO-mOat1, mOat1-transfected CHO; CHO-mOat3, mOat3-transfected CHO; hOCT2, human organic cation transporter 2; HPLC, high-performance liquid chromatography; mOat1, murine organic anion transporter 1; mOat3, murine organic anion transporter 3; OAT/Oat, organic anion transporter; OAT1/hOAT1, human organic anion transporter 1; OAT3/hOAT3, human organic anion transporter 3; Oat3(-/-), Oat3 null; Vdss, apparent volume of distribution at steady state; Vmax, maximum transport rate; ANOVA, analysis of variance; HEK, human embryonic kidney; MUSC, Medical University of South Carolina; M1, desethyleneciprofloxacin; M2, sulfociprofloxacin; M3, oxociprofloxacin; M4, formylciprofloxacin.
- Received October 19, 2007.
- Accepted March 31, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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