Competitive Inhibition of Renal Tubular Secretion of Gemifloxacin by Probenecid

Abstract

Probenecid interacts with transport processes of drugs at several sites in the body. For most quinolones, renal clearance is reduced by concomitant administration of probenecid. The interaction between gemifloxacin and probenecid has not yet been studied. We studied the extent, time course, site(s), and mechanism of this interaction. Seventeen healthy volunteers participated in a randomized, two-way crossover study. Subjects received 320 mg gemifloxacin as an oral tablet without and with 4.5 g probenecid divided in eight oral doses. Drug concentrations in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry. WinNonlin was used for noncompartmental analysis, compartmental modeling, and statistics, and NONMEM was used for visual predictive checks. Concomitant administration of probenecid increased plasma gemifloxacin concentrations and amounts excreted in urine compared to baseline amounts. Data are average estimates (percent coefficients of variation). Modeling showed a competitive inhibition of the renal tubular secretion of gemifloxacin by probenecid as the most likely mechanism of the interaction. The estimated K m and V max for the saturable part of renal elimination were 9.16 mg/liter (20%) and 113 mg/h (21%), respectively. Based on the molar ratio, the affinity for the renal transporter was 10-fold higher for gemifloxacin than for probenecid. Since probenecid reached an ϳ200-times-higher area under the molar concentration-time curve from 0 to 24 h than gemifloxacin, probenecid inhibited the active tubular secretion of gemifloxacin. Probenecid also reduced the nonrenal clearance of gemifloxacin from 25.2 (26%) to 21.0 (23%) liters/h. Probenecid inhibited the renal tubular secretion of gemifloxacin, most likely by a competitive mechanism, and slightly decreased nonrenal clearance of gemifloxacin.Gemifloxacin is a fluoronaphthyridone antimicrobial with an enhanced activity against gram-positive pathogens (7). It is approved by the FDA for treatment of acute bacterial exacerbations of chronic bronchitis and mild to moderate communityacquired pneumonia. Renal clearance of gemifloxacin exceeds the glomerular filtration rate, which indicates net tubular secretion (2). As gemifloxacin exists primarily as a zwitterion at physiological pH, it is likely to interact with organic anion transporters (OATs) and organic cation transporters (OCTs) in renal tubular cells (31). Probenecid is known to inhibit active transport processes of anionic and cationic drug molecules at several sites in the body (13,15,16). Probenecid is well documented to decrease the renal secretion of many quinolones, e.g., gatifloxacin (21), levofloxacin (10, 11), and ciprofloxacin (14). However, there are no reports on the interaction between probenecid and gemifloxacin.For studies of the time course and mechanism of a drugdrug interaction, compartmental modeling is superior to standard noncompartmental analysis (NCA). In addition to having other limitations, standard NCA does not allow one to predict the interaction for...

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