Organic anion transporter 3 (oat3/slc22a8) interacts with carboxyfluoroquinolones, and deletion increases systemic exposure to ciprofloxacin.
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 (K(m) value, 70 +/- 6 microM) 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 microM, 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.
Vanwert
Adam L
AL
Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, 280 Calhoun Street, P.O. Box 250140, Charleston, SC 29425, USA.
Srimaroeng
Chutima
C
Sweet
Douglas H
DH
D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001692:Biological Transport / Q000187:drug effects; D016466:CHO Cells; D002939:Ciprofloxacin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005260:Female; D017353:Gene Deletion; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections; D009865:Oocytes / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015363:Quinolones / Q000378:metabolism*; D014982:Xenopus laevis
D000890:Anti-Infective Agents; D029362:Organic Anion Transporters, Sodium-Independent; D015363:Quinolones; C114338:organic anion transport protein 3; D002939:Ciprofloxacin