Capacity-limited renal glucuronidation of probenecid by humans

Vree, T.B.; Kolmer, E.W.J. van Ewijk-Beneken; Wuis, E.W.

doi:10.1007/bf01977622

Cited by 15 publications

(18 citation statements)

References 39 publications

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“…One-and two-compartment disposition models with parallel first-order and mixed-order elimination pathways were tested, since saturable elimination of probenecid has been reported previously (9,34). The oral absorption was described as a first-order process with or without a lag time.…”

Section: Methodsmentioning

confidence: 99%

Competitive Inhibition of Renal Tubular Secretion of Gemifloxacin by Probenecid

Landersdorfer

Kirkpatrick

Kinzig

et al. 2009

Antimicrob Agents Chemother

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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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Section: Methodsmentioning

confidence: 99%

Competitive Inhibition of Renal Tubular Secretion of Gemifloxacin by Probenecid

Landersdorfer

Kirkpatrick

Kinzig

et al. 2009

Antimicrob Agents Chemother

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“…Several studies have been published indicating that probenecid given one to three times daily at doses ranging from 250 to 1,000 mg can result in significant increases in the plasma concentrations of other approved medications (7,15,17,22,23). Probenecid demonstrates dose-dependent pharmacokinetics and nonlinear elimination (10,35).…”

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confidence: 99%

Pharmacokinetics and Tolerability of Oseltamivir Combined with Probenecid

Holodniy

Penzak

Straight

et al. 2008

Antimicrob Agents Chemother

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Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg probenecid four times a day (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid twice a day (group 3) for 15 days. Pharmacokinetic data, obtained by noncompartmental methods, and safety data are reported. Forty-eight subjects completed the pharmacokinetic analysis. The study drugs were generally well tolerated, except for one case of reversible grade 4 thrombocytopenia in a subject in group 2. The calculated 90% confidence intervals (CIs) for the geometric mean ratios between groups 2 and 3 and group 1 were outside the bioequivalence criteria boundary (0.80 to 1.25) at 0.63 to 0.89 for group 2 versus group 1 and 0.57 to 0.90 for group 3 versus group 1. The steady-state apparent oral clearance of oseltamivir carboxylate was significantly less in groups 2 (7.4 liters/h; 90% CI, 6.08 to 8.71) and 3 (7.19 liters/h; 90% CI, 6.41 to 7.98) than in group 1 (9.75 liters/h; 90% CI, 6.91 to 12.60) (P < 0.05 for both comparisons by analysis of variance). The (arithmetic) mean concentration at 48 h for group 2 was not significantly different from the mean concentration at 24 h for group 1 (42 ؎ 76 and 81 ؎ 54 ng/ml, respectively; P ‫؍‬ 0.194), but the mean concentration at 48 h for group 3 was significantly less than the mean concentration at 24 h for group 1 (23 ؎ 26 and 81 ؎ 54 ng/ml, respectively; P ‫؍‬ 0.012). Alternate-day dosing of oseltamivir plus dosing with probenecid four times daily achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro, and this combination should be studied further.

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“…One-and two-compartment disposition models with parallel first-order and mixed-order elimination pathways were considered for probenecid, since saturable elimination of probenecid has been reported previously [16,17]. The oral absorption of probenecid was described as firstorder process with or without a lag time.…”

Section: Absorption and Disposition Of Probenecidmentioning

confidence: 99%

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

Landersdorfer

Kirkpatrick

Kinzig

et al. 2010

Brit J Clinical Pharma

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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. AIMSProbenecid 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. METHODSA 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®. RESULTSData 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. CONCLUSIONSProbenecid 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.

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Capacity-limited renal glucuronidation of probenecid by humans

Cited by 15 publications

References 39 publications

Competitive Inhibition of Renal Tubular Secretion of Gemifloxacin by Probenecid

Competitive Inhibition of Renal Tubular Secretion of Gemifloxacin by Probenecid

Pharmacokinetics and Tolerability of Oseltamivir Combined with Probenecid

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

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