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Randomized Controlled Trial
. 2010 Feb;69(2):167-78.
doi: 10.1111/j.1365-2125.2009.03564.x.

Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid

Cornelia B Landersdorfer  1 , Carl M J Kirkpatrick, Martina Kinzig, Jürgen B Bulitta, Ulrike Holzgrabe, Ulrich Jaehde, Andreas Reiter, Kurt G Naber, Michael Rodamer, Fritz Sörgel
Affiliations
Randomized Controlled Trial

Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid

Cornelia B Landersdorfer et al. Br J Clin Pharmacol. 2010 Feb.

Abstract

Aims: Probenecid influences transport processes of drugs at several sites in the body and decreases elimination of several quinolones. We sought to explore extent, time course, and mechanism of the interaction between ciprofloxacin and probenecid at renal and nonrenal sites.

Methods: A randomized, two-way crossover study was conducted in 12 healthy volunteers (in part previously published Clin Pharmacol Ther 1995; 58: 532-41). Subjects received 200 mg ciprofloxacin as 30-min intravenous infusion without and with 3 g probenecid divided into five oral doses. Drug concentrations were analysed by liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography. Ciprofloxacin and its 2-aminoethylamino-metabolite (M1) in plasma and urine with and without probenecid were modelled simultaneously with WinNonlin.

Results: Data are ratio of geometric means (90% confidence intervals). Addition of probenecid reduced the median renal clearance from 23.8 to 8.25 l h(-1)[65% reduction (59, 71), P < 0.01] for ciprofloxacin and from 20.5 to 8.26 l h(-1) (66% reduction (57, 73), P < 0.01] for M1 (estimated by modelling). Probenecid reduced ciprofloxacin nonrenal clearance by 8% (1, 14) (P < 0.08). Pharmacokinetic modelling indicated competitive inhibition of the renal tubular secretion of ciprofloxacin and M1 by probenecid. The affinity for the renal transporter was 4.4 times higher for ciprofloxacin and 3.6 times higher for M1 than for probenecid, based on the molar ratio. Probenecid did not affect volume of distribution of ciprofloxacin or M1, nonrenal clearance or intercompartmental clearance of ciprofloxacin.

Conclusions: Probenecid inhibited the renal tubular secretion of ciprofloxacin and M1, probably by a competitive mechanism and due to reaching >100-fold higher plasma concentrations. Formation of M1, nonrenal clearance and distribution of ciprofloxacin were not affected.

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Figures

Figure 2
Figure 2
Compartmental model. (a) Treatment without probenecid. (b) Treatment with probenecid
Figure 1
Figure 1
Ciprofloxacin, ciprofloxacin-M1 and probenecid plasma concentrations and amounts in urine (average ± standard deviation). Lines represent average predicted concentrations and amounts in urine of the model with competitive interaction for renal elimination
See this image and copyright information in PMC

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