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

Landersdorfer, Cornelia B., Kirkpatrick, Carl M. J., Kinzig, Martina, Bulitta, Jürgen B., Holzgrabe, Ulrike, Jaehde, Ulrich, Reiter, Andreas, Naber, Kurt G., Rodamer, Michael and Sorgel, Fritz (2010) Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid. British Journal of Clinical Pharmacology, 69 2: 167-178. doi:10.1111/j.1365-2125.2009.03564.x


Author Landersdorfer, Cornelia B.
Kirkpatrick, Carl M. J.
Kinzig, Martina
Bulitta, Jürgen B.
Holzgrabe, Ulrike
Jaehde, Ulrich
Reiter, Andreas
Naber, Kurt G.
Rodamer, Michael
Sorgel, Fritz
Title Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid
Journal name British Journal of Clinical Pharmacology   Check publisher's open access policy
ISSN 0306-5251
1365-2125
Publication date 2010-02
Year available 2009
Sub-type Article (original research)
DOI 10.1111/j.1365-2125.2009.03564.x
Volume 69
Issue 2
Start page 167
End page 178
Total pages 12
Place of publication London, United Kingdom
Publisher Blackwell Science
Collection year 2011
Language eng
Subject C1
110309 Infectious Diseases
920109 Infectious Diseases
Formatted abstract
What is already know about this subject
• Probenecid inhibits the active transport of both anionic and cationic drug molecules at various sites in the body.

• Probenecid has been reported to decrease the elimination of several quinolones.

• We are not aware of any reports where a mechanism-based model for the interaction of quinolones and probenecid in humans or animals has been developed.

What this study adds
• Pharmacokinetic modelling indicates competitive inhibition of the renal tubular secretion of ciprofloxacin and its metabolite M1 by probenecid.

• The affinity for the renal transporter was 4.4 times higher for ciprofloxacin and 3.6 times higher for M1 compared with probenecid, based on molar concentrations.

• Probenecid did not affect volume of distribution of ciprofloxacin or M1, nonrenal clearance or intercompartmental clearance of ciprofloxacin.

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.
Copyright © 1999–2011 John Wiley & Sons, Inc. All Rights Reserved.
Keyword Ciprofloxacin
Competitive inhibition
Metabolite formation
Modelling of pharmacokinetic interaction
Probenecid
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Article first published online: 23 Oct 2009

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
School of Pharmacy Publications
 
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Created: Sun, 07 Feb 2010, 00:08:13 EST