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

WHAT IS ALREADY KNOWN 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