Clinical Pharmacokinetics of Probenecid

@article{Cunningham1981ClinicalPO,
  title={Clinical Pharmacokinetics of Probenecid},
  author={R. F. Cunningham and Zafar H. Israili and Peter G. Dayton},
  journal={Clinical Pharmacokinetics},
  year={1981},
  volume={6},
  pages={135-151}
}
SummaryA review of the clinical applications and of the disposition of probenecid in man, including drug interactions, is presented.Probenecid is the classical competitive inhibitor of organic acid transport in the kidney and other organs. There are 2 primary clinical uses for probenecid: as a uricosuric agent in the treatment of chronic gout and as an adjunct to enhance blood levels of antibiotics (such as penicillins and Cephalosporins). Adsorption of probenecid is essentially complete… 
Interindividual variation in the capacity-limited renal glucuronidation of probenecid by humans
TLDR
It was inferred that probenecid acyl glucuronide is formed in the kidney during blood-to-lumen passage through the tubular cells and the plateau value in the renal excretion rate-time profile reflects itsVmax of formation.
Probenecid-induced changes in the clearance of pranoprofen enantiomers.
TLDR
Probenecid had a slight effect on the tissue distribution of pranoprofen at the dose used, but significantly reduced the formation of glucuronide for both enantiomers to the same extent in kidney microsomes.
Effect of probenecid on the formation and elimination kinetics of the sulphate and glucuronide conjugates of diflunisal
TLDR
Steady state plasma concentrations of the sulphate and glucuronide conjugates of diflunisal were 2.5- to 3.1-fold higher during probenecid co-administration, due to a significant reduction in the renal clearance of the three dif lunisal conjugate.
Effects of probenecid on the pharmacokinetics and elimination of acyclovir in humans
TLDR
It is confirmed that acyclovir is eliminated predominantly by renal clearance, both by glomerular filtration and tubular secretion; the results suggested that at least part of thetubular secretion is inhibited by probenecid.
The effect of probenecid on the renal elimination of cimetidine
TLDR
The study demonstrates that renal interactions between organic cations and organic anions can occur in human beings and the mechanism of this interaction and the implications to other drug combinations are being explored.
Probenecid: its chromatographic determination, plasma protein binding, and in vivo pharmacokinetics in dogs.
TLDR
Observation in relation to plasma protein binding and PK parameters will serve as the basic information concerning drug-drug interactions in dogs and in other mammalian species.
The effect of probenecid on the renal tubular excretion of benzylpenicillin.
TLDR
Extrapolating these results to the clinical situation, the commonly used daily dose of 2 g of probenecid is likely to be close to the maximal effective dose for inhibition of the tubular excretion of benzylpenicillin.
Pharmacology of drugs for hyperuricemia. Mechanisms, kinetics and interactions.
  • F. Pea
  • Medicine
    Contributions to nephrology
  • 2005
TLDR
Rasburicase probably undergoes peptide hydrolysis and in in vitro studies was shown neither to inhibit or induce cytochrome P450 isoenzymes nor to interact with several drugs, so that no relevant interaction is expected during cotreatment in patients.
Effect of probenecid on the pharmacokinetics of cefmenoxime
TLDR
Tubular secretion is the predominant mechanism of clearance for cefmenoxime and that probenecid alters the pharmacokinetics of the compound by competitively inhibiting its tubular secretion without affecting either the rate or the extent of its distribution.
Capacity-limited renal glucuronidation of probenecid by humans
TLDR
Probenecid shows dose-dependent pharmacokinetics and it is demonstrated that probenecid glucuronide must be formed in the kidney during its passage of the tubule, and the plateau value in the renal excretion rate-time profile shows itsVmax of formation.
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References

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The effect of the interaction of pyrazinamide and probenecid on urinary uric acid excretion in man.
Complex interactions occur between pyrazinamide (PZA) and probenecid in man involving both the metabolism and distribution of the drugs, and their effects on renal tubules. Pretreatment with PZA
Urinary excretion of probenecid and its metabolites in humans as a function of dose.
TLDR
A prolonged time course of excretion of the metabolites, particularly at higher doses, suggests that probenecid, being poorly soluble in water, precipitates from solution in the GI tract, forming a depot of drug from which absorption is dissolution rate limited.
The physiological disposition of probenecid, including renal clearance, in man, studied by an improved method for its estimation in biological material.
TLDR
Probenecid was found to be rapidly and fairly completely absorbed from the human gastrointestinal tract and the half-life studies indicate that the drug must be transformed to unknown metabolites or conjugates.
THE METABOLISM OF PROBENECID IN MAN *
  • P. Dayton, J. Perel
  • Chemistry, Medicine
    Annals of the New York Academy of Sciences
  • 1971
TLDR
The metabolic fate of probenecid in man has recently been elucidated in the laboratory by determining the chemical structures of the urinary metabolites and their pattern of excretion, and it was determined that the clearance of the drug in man was dependent on urine flow and pH.
Biliary excretion of probenecid and its glucuronide.
TLDR
Findings suggest that, at the low dose, phenolphthalein acted primarily on the transport of unchanged probenecid and, on the higher dose, on uridine diphosphate glucuronyl transferase.
Identification and renal excretion of probenecid metabolites in man.
TLDR
The metabolic fate of probenecid (p-(dipropylsulfamoyl) benzoic acid) in man has been elucidated by determining the chemical structures of the urinary metabolites and their pattern of excretion using quantitative thin-layer chromatography.
Probenecid: an unexplained effect on cephalosporin pharmacology.
TLDR
Urinary excretion of antibiotic activity was slightly but not significantly decreased by probenecid during the initial 6 h postdosing, but it was significantly increased in 6-12 h urine, but only a small percentage of the doses were excreted during that period.
Impairment of hepatic uptake of rifamycin antibiotics by probenecid, and its therapeutic implications.
TLDR
Rifamycins and probenecid were shown to have similar effects in depressing the hepatic uptake of bromsulphthalein and bilirubin in rats, and these effects were not due to competition for binding to ligandin and Z acceptor proteins, and possibly involve competition at the plasma membrane.
Influence of probenecid and spironolactone on furosemide kinetics and dynamics in man
TLDR
The relationship ~f furosemide kinetics to dynamics observed in these studies confirms that, in man, the diuretic response is determined by drug that reaches the renal tubule rather than the drug level in plasma.
Studies of the fate of metabolites and analogs of probenecid. The significance of metabolic sites, especially lack of ring hydroxylation.
TLDR
The results with probenecid and its analog suggest that molecular modification of drugs could be oriented in such a way as to prevent ring oxidation, but without loss of pharmacologic activity.
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