Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, September 2009, p. 3902-3907, Vol. 53, No. 9
0066-4804/09/$08.00+0 doi:10.1128/AAC.01200-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Competitive Inhibition of Renal Tubular Secretion of Gemifloxacin by Probenecid
Cornelia B. Landersdorfer,1,
Carl M. J. Kirkpatrick,2
Martina Kinzig,1
Jürgen B. Bulitta,1,
Ulrike Holzgrabe,3
George L. Drusano,4 and
Fritz Sörgel1,5*
IBMP—Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany,1 The University of Queensland, School of Pharmacy, Brisbane, Australia,2 Institute for Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany,3 Ordway Research Institute, Albany, New York,4 Department of Pharmacology, University of Duisburg-Essen, Essen, Germany5
Received 9 September 2008/ Returned for modification 29 March 2009/ Accepted 22 June 2009
Probenecid interacts with transport processes of drugs at several sites in the body. For most quinolones, 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 an oral tablet without and with 4.5 g probenecid divided in eight oral doses. Drug concentrations in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry. WinNonlin was used for noncompartmental analysis, compartmental modeling, and statistics, and NONMEM was used for visual predictive checks. Concomitant administration of probenecid increased plasma gemifloxacin concentrations and amounts excreted in urine compared to baseline amounts. Data are average estimates (percent coefficients of variation). Modeling showed a competitive inhibition of the renal tubular secretion of gemifloxacin by probenecid as the most likely mechanism of the interaction. The estimated Km and Vmax for the saturable part of renal elimination were 9.16 mg/liter (20%) and 113 mg/h (21%), respectively. Based on the molar ratio, the affinity for the renal transporter was 10-fold higher for gemifloxacin than for probenecid. Since probenecid reached an 
200-times-higher area under the molar concentration-time curve 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 (23%) liters/h. Probenecid inhibited the renal tubular secretion of gemifloxacin, most likely by a competitive mechanism, and slightly decreased nonrenal clearance of gemifloxacin.
* Corresponding author. Mailing address: IBMP—Institute for Biomedical and Pharmaceutical Research, Paul-Ehrlich-Str. 19, D-90562 Nürnberg-Heroldsberg, Germany. Phone: 49-911-518290. Fax: 49-911-5182920. E-mail: ibmp{at}osn.de
Published ahead of print on 29 July 2009.
Present address: Ordway Research Institute, Albany, NY.
Antimicrobial Agents and Chemotherapy, September 2009, p. 3902-3907, Vol. 53, No. 9
0066-4804/09/$08.00+0 doi:10.1128/AAC.01200-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Copyright © 2009 by the American Society for Microbiology. For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»