| Title | Competitive inhibition of renal tubular secretion of gemifloxacin by probenecid. | | Author(s) | Landersdorfer CB, Kirkpatrick CM, Kinzig M, Bulitta JB, Holzgrabe U, Drusano GL, Sörgel F | | Institution | IBMP - Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany; The University of Queensland, School of Pharmacy, Brisbane, Australia; Institute for Pharmacy and Food Chemistry, University of Würzburg, Germany; Ordway Research Institute, Albany, New York, USA; Department of Pharmacology, University of Duisburg-Essen, Germany. | | Source | Antimicrob Agents Chemother 2009 Jun 29. | | Abstract | Probenecid interacts with transport processes of drugs at several sites in the body. For most quinolones the renal clearance is reduced by concomitant administration of probenecid. The interaction between gemifloxacin and probenecid has not yet been studied. We studied the extent, time course, site(s), and mechanism of this interaction. Seventeen healthy volunteers participated in a randomized, two-way crossover study. Subjects received 320 mg gemifloxacin as oral tablet without and with 4.5 g probenecid divided in eight oral doses. Drug concentrations in plasma and urine were analyzed by LC-MS/MS. WinNonlin(R) was used for non-compartmental analysis, compartmental modeling and statistics and NONMEM for visual predictive checks. Concomitant administration of probenecid increased gemifloxacin plasma concentrations and amounts excreted in urine compared to baseline. Data are average estimates (% coefficient of variation). Modeling showed a competitive inhibition of the renal tubular secretion of gemifloxacin by probenecid as most likely mechanism of the interaction. The estimated Km and Vmax for the saturable part of renal elimination were 9.16 mg/L (20%) and 113 mg/h (21%). Based on the molar ratio, the affinity for the renal transporter was 10-fold higher for gemifloxacin. As probenecid reached approximately 200-times higher area under the molar concentration-time curves from 0 to 24 h than gemifloxacin, probenecid inhibited the active tubular secretion of gemifloxacin. Probenecid also reduced the nonrenal clearance of gemifloxacin from 25.2 (26%) to 21.0 L/h (23%). Probenecid inhibited the renal tubular secretion of gemifloxacin most likely by a competitive mechanism and slightly decreased nonrenal clearance of gemifloxacin. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19564368 |
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