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

Landersdorfer, Cornelia B.; Kirkpatrick, Carl M.; Kinzig, Martina; Bulitta, Jürgen B.; Holzgrabe, Ulrike; Jaehde, Ulrich; Reiter, Andreas; Naber, Kurt G.; Rodamer, Michael; Sörgel, Fritz

doi:10.1111/j.1365-2125.2009.03564.x

Cited by 44 publications

(21 citation statements)

References 31 publications

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“…Tubular secretion presents another potential site of interaction of these quinolones. As peak ciprofloxacin concentrations for the 500 mg dose in this study were approximately 2.8-fold lower than the Michaelis-Menten constant for saturable renal clearance (6.45 mg/l) estimated by Landersdorfer et al [54], this study was unlikely to find a notable saturation of tubular secretion clearance. Due to the small extent of interaction, the present dataset did not support estimation of models with saturable tubular secretion in addition to a saturable reabsorption.…”

Section: Discussionmentioning

confidence: 55%

Population Pharmacokinetics and Penetration into Prostatic, Seminal, and Vaginal Fluid for Ciprofloxacin, Levofloxacin, and Their Combination

et al. 2011

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Background: Our objectives were to assess the pharmacokinetic interaction and body fluid penetration of ciprofloxacin and levofloxacin. Methods: This study was a single-dose open randomized three-way crossover in 15 healthy volunteers receiving 500 mg oral levofloxacin, 500 mg oral ciprofloxacin, or 250 mg levofloxacin and 250 mg ciprofloxacin co-administered. Serum, urine, and body fluid concentrations were determined by high-performance liquid chromatography and analyzed via population pharmacokinetic modeling. Results: Modeling indicated that ciprofloxacin inhibited the renal reabsorption of levofloxacin. Ciprofloxacin increased the net renal clearance of levofloxacin by 13%, as its estimated affinity for a putative tubular reabsorption transporter was 12-fold higher (Km: 568 µM) compared to levofloxacin (Km: 6,830 µM). Levofloxacin increased the bioavailability of ciprofloxacin by 12% and achieved significantly (p < 0.05) higher concentrations at 3 h in ejaculate, prostatic, seminal, and vaginal fluid compared to ciprofloxacin. Conclusion: Modeling suggested that ciprofloxacin inhibited the tubular reabsorption of levofloxacin due to a 12-fold higher affinity for a putative tubular reabsorption transporter compared to levofloxacin. This pharmacokinetic interaction was not clinically relevant.

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Section: Discussionmentioning

confidence: 55%

Population Pharmacokinetics and Penetration into Prostatic, Seminal, and Vaginal Fluid for Ciprofloxacin, Levofloxacin, and Their Combination

et al. 2011

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“…Several studies have revealed the impacts of metabolism mediated by cytochrome P450 isoform 3A (CYP3A) and of renal excretion mediated by OAT and P-glycoprotein (P-gp) on the pharmacokinetic alteration of drugs (Laskin et al, 1982;Vree et al, 1995;Hsu et al, 1998;Ouellet et al, 1998;Landersdorfer et al, 2010;Schmitt et al, 2010); however, other processes such as transcellular dynamics regulated by other transporters cannot be ignored. OCT and MATE have been also evaluated in several studies (Yonezawa and Inui, 2011).…”

Section: Discussionmentioning

confidence: 99%

Potential Drug Interactions Mediated by Renal Organic Anion Transporter OATP4C1

Sato¹,

Mishima²,

Mano³

et al. 2017

J Pharmacol Exp Ther

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Organic anion-transporting polypeptide 4C1 (OATP4C1) is an organic anion transporter expressed in the basolateral membrane of the renal proximal tubules. It plays a major role in the urinary excretion of both exogenous drugs and endogenous compounds. Our previous studies have indicated the importance of OATP4C1 in pathologic and physiologic conditions; however, the majority of its pharmacologic characteristics remained unclear. Therefore, to provide essential information for clinical drug therapy decisions and drug development, we clarified drug interactions mediated by OATP4C1. To elucidate potential drug interactions via OATP4C1, we screened 53 representative drugs commonly used in clinical settings. Next, we evaluated the IC values of drugs that inhibited OATP4C1 by more than 50%. To apply our results to clinical settings, we calculated the drug-drug interaction (DDI) indices. The screening analysis using an OATP4C1-expressing cell system demonstrated that 22 out of 53 therapeutic drugs inhibited OATP4C1-mediated triiodothyronine transport. In particular, OATP4C1-mediated transport was strongly inhibited by 10 drugs. The IC values of 10 drugs-nicardipine, spironolactone, fluvastatin, crizotinib, levofloxacin, clarithromycin, ritonavir, saquinavir, quinidine, and verapamil-obtained in this study were 51, 53, 41, 24, 420, 200, 8.5, 4.3, 100, and 110 M, respectively. The IC values of these drugs were higher than the plasma concentrations obtained in clinical practice. However, ritonavir showed the highest DDI index (1.9) for OATP4C1, suggesting that it may strongly influence this transporter and thus cause drug interactions seen in clinical settings. Our finding gives new insight into the role of OATP4C1 in clinical DDIs.

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“…One-, two-, and three-compartment disposition models were considered. Competing models were distinguished by their predictive performance, assessed via visual predictive checks, their objective function value, the plausibility of parameter estimates, and standard diagnostic plots (25,26).…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetics of Piperacillin at Two Dose Levels: Influence of Nonlinear Pharmacokinetics on the Pharmacodynamic Profile

Landersdorfer

Bulitta

Kirkpatrick

et al. 2012

Antimicrob Agents Chemother

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g Piperacillin in combination with tazobactam is one of the most commonly used intravenous antibiotics. There is evidence for a possible saturable elimination of piperacillin. Therefore, the saturable elimination and its impact on the choice of optimal dosage regimens were quantified. In a randomized crossover study, 10 healthy volunteers received 1,500 mg and 3,000 mg of piperacillin as 5-min intravenous infusion. Population pharmacokinetics based on plasma and urine data were determined utilizing NONMEM and S-ADAPT. Probabilities of target attainment (PTAs) were compared for different models and dosage regimens, based on the target time of the non-protein-bound concentration above the MIC of at least 50% of the dosing interval. Total clearance of piperacillin was 18% (geometric mean ratio, 90% confidence interval, 11 to 24%) lower (P < 0.01), and renal clearance was 24% (9 to 37%) lower (P ‫؍‬ 0.02) at the high compared to the low dose. The final model included first-order nonrenal elimination and parallel first-order and mixed-order renal elimination. Nonrenal clearance was 5.44 liter/h (coefficient of variation, 18%), first-order renal clearance was 4.42 liter/h (47%), and the maximum elimination rate of mixed-order renal elimination was 219 mg/h (84%), with a Michaelis-Menten constant of 36.1 mg/liter (112%). Compared to models with saturable elimination, a linear model predicted up to 10% lower population PTAs for high-dose short-term infusions (6 g every 8 h) and up to 4% higher population PTAs for low-dose continuous infusions (6 g/day). While renal elimination of piperacillin was saturable at therapeutic concentrations, the extent of saturation of nonrenal clearance was small. The influence of saturable elimination on PTAs for clinically relevant dosage regimens was relatively small. P iperacillin in combination with the beta-lactamase inhibitor tazobactam is one of the most frequently used intravenous antibiotic choices. It is bactericidal against Gram-positive microorganisms and Pseudomonas aeruginosa (37) and is frequently used in the empirical treatment of hospital-acquired infections. It has sufficient stability at room temperature (39), which makes it attractive for prolonged or continuous infusion. During the use of piperacillin for more than 2 decades, there have been discussions about whether a clinically significant saturable elimination pathway exists (5,6,9,10,20,30,41). There is evidence (12,27,36,40) that the renal tubular secretion of piperacillin is saturable at therapeutic concentrations. Saturable elimination of antibiotics may be clinically important and affect the choice of optimal dosage regimen, and it may be more pronounced for specific dose levels and dosage regimens. However, the impact of potentially saturable piperacillin elimination on probabilities of target attainment (PTAs) has not been studied previously.Our first objective was to assess the potentially saturable renal and nonrenal elimination of piperacillin in a well-controlled healthy volunteer crossover study at two d...

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

Cited by 44 publications

References 31 publications

Population Pharmacokinetics and Penetration into Prostatic, Seminal, and Vaginal Fluid for Ciprofloxacin, Levofloxacin, and Their Combination

Population Pharmacokinetics and Penetration into Prostatic, Seminal, and Vaginal Fluid for Ciprofloxacin, Levofloxacin, and Their Combination

Potential Drug Interactions Mediated by Renal Organic Anion Transporter OATP4C1

Population Pharmacokinetics of Piperacillin at Two Dose Levels: Influence of Nonlinear Pharmacokinetics on the Pharmacodynamic Profile

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