New Insights into the Most Commonly Studied Drug Interaction with Antibiotics: Pharmacokinetic Interaction between Ciprofloxacin, Gemifloxacin and Probenecid at Renal and Non-renal Sites
Landersdorfer, C.(1), C. M. J. Kirkpatrick(2), M. Kinzig-Schippers(1), J. Bulitta(1), U. Holzgrabe(3), F. Sörgel(1,4)
(1)IBMP, Nürnberg, Germany; (2)Univ. of Queensland, Brisbane, Australia; (3)Univ. of Würzburg, Würzburg, Germany; (4)Univ. of Duisburg-Essen, Essen, Germany;
Objectives: Probenecid interacts with transport processes of drugs at several sites in the body. We modeled gemifloxacin in plasma and urine with and without probenecid simultaneously and compared it to the simultaneous model of ciprofloxacin (CIP), its metabolite CIP-M1, and probenecid (=re-analysis of CIP data from Clin Pharmacol Ther. 1995 58:532-41, not done then). This allowed us to compare the extent, time course, and mechanism of the quinolone-probenecid interaction at the renal and non-renal sites between CIP and gemifloxacin. Additionally, we studied the effect of probenecid on the formation of CIP-M1.
Methods: We ran two randomized, two-way crossover studies in healthy volunteers (CIP 6M / 6F; gemifloxacin 9M / 8F). Study 1: 200 mg CIP as 30 min iv infusion without and with 3 g probenecid divided in five oral doses. Study 2: 320 mg oral gemifloxacin without and with 4.5 g probenecid divided in eight oral doses. Drug analysis by LC-MS/MS and HPLC. We used non-compartmental analysis and modeled the full time course of gemifloxacin and probenecid as well as of CIP, CIP-M1 and probenecid in plasma and urine simultaneously with WinNonlin(R). We used ANOVA statistics.
Results: Data are ratio of geometric means [90% confidence intervals] (*=p<0.01).
Addition of probenecid reduced the renal clearance to 35% [29-41%]* of baseline for CIP, to 34% [27-43%]* for CIP-M1 (estimated by modeling) and to 49% [47-51%]* for gemifloxacin. Probenecid reduced the non-renal clearance to 81% [74-88%]* for gemifloxacin and to 92% [86-99%] (p<0.08) for CIP. Pharmacokinetic modeling showed a competitive inhibition of the renal tubular secretion of CIP by probenecid. The affinity for the renal transporter was 3.8 fold higher (median) for CIP than for probenecid and 7.2 fold higher for gemifloxacin than for probenecid. Our models indicated that probenecid inhibited the non-renal clearance of gemifloxacin, but did not affect the non-renal clearance of CIP or the formation of CIP-M1.
Conclusions: Simultaneous modeling of the full time course of gemifloxacin and probenecid as well as of CIP, CIP-M1 and probenecid as expected was superior to non-compartmental analysis in providing insight into the mechanisms of the interactions. Probenecid inhibited the renal secretion of gemifloxacin, CIP and CIP-M1 and slightly decreased the non-renal clearance of gemifloxacin.