Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid.
OBJECTIVE
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.
Landersdorfer
Cornelia B
CB
IBMP--Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany.
Kirkpatrick
Carl M J
CM
Kinzig
Martina
M
Bulitta
Jürgen B
JB
Holzgrabe
Ulrike
U
Jaehde
Ulrich
U
Reiter
Andreas
A
Naber
Kurt G
KG
Rodamer
Michael
M
Sörgel
Fritz
F
D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000704:Analysis of Variance; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008954:Models, Biological; D011339:Probenecid / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D013223:Statistics as Topic
D000277:Adjuvants, Pharmaceutic; D000890:Anti-Infective Agents; D002939:Ciprofloxacin; D011339:Probenecid