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PubMed1980

Use of probenecid in ticarcillin-induced hypokalemia.

Probenecid has been suggested as a prophylactic treatment of penicillin-induced hypokalemia, the proposed mechanism being that penicillin will be prevented from acting as a nonreabsorbable anion binding potassium and resulting in increased urinary losses. A rapidly occurring hypokalemia, unresponsive to intravenous replacement of potassium, can be explained by redistribution rather than urinary wastage. We report a case where probenecid was administered for ticarcillin-induced hypokalemia without any significant benefits.

Child↗

PubMedDate not supplied

Effect of cimetidine, probenecid, and ketoconazole on the distribution, biliary secretion, and metabolism of [3H]taxol in the Sprague-Dawley rat.

Male Sprague-Dawley rats had their bile ducts cannulated and were dosed with [3H]taxol (2 mg/kg, 68-77 microCi/mg) as a continuous intravenous infusion for 6 hr so that the plasma concentrations, tissue distribution, metabolism, and biliary secretion of taxol could be studied. Defining potential drug-drug interactions of taxol with cimetidine (90 mg/kg), probenecid (360 mg/kg), and ketoconazole (50 mg/kg) was motivated by frequent concomitant clinical use or the potential to reduce clearance of taxol so that lower doses could be used. At 6 hr, rats were killed. Samples of blood (plasma), lung, spleen, liver, kidney, heart, skeletal muscle, brain, testes, and fat were obtained. Taxol and metabolites were measured by total radioactivity counting and HPLC separation using on-line radioactivity detection. Concentrations of taxol in plasma increased to 0.19 microM in the control rats and did not reach steady-state by 6 hr. Lung, spleen, liver, and kidneys had the greatest tissue taxol concentrations [4.7-5.7 nmol/g (microM)] and were > 25-fold higher than the simultaneous 6-hr plasma taxol concentration. Taxol concentrations in brain and testes were negligible, 0.06 and 0.07 nmol/g, respectively. Radioactive metabolites were not found in plasma or most tissues. Only liver had appreciable concentrations of taxol and metabolites; however, > 80% of hepatic radioactivity was parent taxol. Through 6 hr of collection, 24% of the dose was secreted in the bile approximately 38% of which was as parent taxol. Cimetidine had no effect on the distribution, metabolism, or elimination of [3H]taxol. Probenecid did not effect tissue distribution or plasma concentrations of taxol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1976

Treatment of gonorrhoea with a combination of probenecid and procaine penicillin in Rwanda.

Treatment of acute gonorrhoea with 1 g of probenecid orally followed after 1 h by 4.8 M-units of procaine penicillin intramuscularly yielded a 97.4% cure in men. The cure rate of 81.8% in women is not so satisfactory but the fact that the patients, mostly prostitutes, were chronically infected must be considered. The incidence of post-gonococcal urethritis in men was 34%. Disc sensitivity of neisseria gonorrhoea showed a similar pattern of mostly resistant strains for streptomycin, as in Uganda and Kenya. Ninety-four per cent of strains are sensitive to penicillin but these results must be confirmed by the more reliable dilution method. It is concluded that the treatment schedule studied, eventually simplified by the administration of probenecid and injections of penicillin simultaneously, can be recommended as a standard treatment for gonorrhoea in Rwanda.

Acute Disease↗

PubMed1976

Different inhibitory effects of 2,4-dinitrophenol, iodoacetate, and probenecid on renal excretion of p-aminohippurate, cyclopenthiazide, and sulfamethoxypyridazine in rats.

The present study was undertaken to determine whether the renal excretion of drugs can be modified by inhibition of the carrier system for organic acids in vivo. The renal excretion of p-aminohippurate is not influenced by 2,4-dinitrophenol but is reduced by iodoacetate and probenecid. The renal excretion of cyclopenthiazide is decreased by all inhibitors. Rats excrete only a very small portion of the administered dose of sulfamethoxypyridazine. Renal sulfamethoxypyridazine excretion is 3 times higher when the tubular reabsorption is blocked by simultaneous administration of NaHCO3. However, even then only a small portion of the injected dose is excreted. Renal sulfamethoxypyridazine excretion is only reduced by probenecid. This finding can be explained by the reduction of the urine volume. It can be concluded that p-aminohippurate and cyclopenthiazide are renally excreted by tubular secretion, whereas sulfamethoxy-pyridazine is excreted by glomerular filtration.

Aminohippuric Acids↗

PubMed1975

Homovanillic acid and 5-hydroxyindoleacetic acid cerebrospinal fluid levels. A study with and without probenecid administration of their relationship to the state of consciousness after head injury.

Homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were measured in the lumbar cerebrospinal fluid of 98 patients after closed head injury. The HVA levels decreased in patients, whether or not they were given the drug probenecid, which inhibits the active transport of these acids from the brain. The decline of HVA was more notable in patients with the longest duration of unconsciousness. The HVA levels showed no correlation with the state of consciousness at the moment of the lumbar puncture. The 5-HIAA levels were below normal in the conscious patients, but paradoxically, at about normal levels in unconscious patients. The overall results suggest a decreased cerebral dopamine and serotonin metabolism after head injury.

Blood-Brain Barrier↗

PubMed1978

Chronic, multiple tics of Gilles de la Tourette's disease. CSF acid monoamine metabolites after probenecid administration.

Central nervous system metabolism in six children and one adult with the syndrome of chronic multiple tics was studied by measuring the accumulation of acid metabolites of dopamine and serotonin (homovanillic acid [HVA] and 5-hydroxyindole-acetic acid [5-HIAA], respectively) in the CSF following probenecid administration. The accumulation of 5-HIAA was reduced in patients with multiple tics in contrast with other pediatric patients (N = 27). The degree of reduction in 5-HIAA relative to HVA appeared to be associated with the severity of the tic disorder. With dextroamphetamine, tic symptoms worsened, CSF HVA level decreased, and CSF 5-HIAA concentration increased. These findings suggest an association in Gilles de la Tourette's disease of reduced functioning of inhibitory serotonergic mechanisms and functional dopaminergic overactivity.

Adolescent↗

PubMed1979

Ticrynafen and probenecid in hyperuricemic, hypertensive men.

In a double-blind crossover study of ticrynafen (TCN) and probenecid (PBC), 9 hypertensive, hyperuricemic men completed 12-wk courses of each drug. With a TCN dose of 125 mg daily, the fall in serum uric acid was prompt, dramatic, and lasting; it was equal to that after PBC, 500 or 1,000 mg daily. There was a small but significant early weight loss (diuresis) after TCN but no antihypertensive effect. Twelve days after resuming TCN for a proposed additional extension study 1 patient suffered acute, reversible bilateral ureteral obstruction, probably caused by sudden urinary uric acid precipitation.

Blood Pressure↗

PubMed1979

Effect of probenecid on cerebrospinal fluid methotrexate kinetics.

The effect of probenecid (PBC) on methotrexate (MTX) kinetics in the cerebrospinal fluid (CSF) and serum was studied in 4 patients on high-dose MTX with leucovorin rescue to determine whether addition of PBC could prolong effective CSF MTX levels. Each patient received 2 courses of MTX, 1 with and 1 without PBC. PBC caused a 2.8 to 4.2-fold increase in CSF MTX concentrations but failed to prolong the CSF half-life (1 1/2). PBC prolonged the initial MTX elimination t 1/2 in the blood from 2.7 to 4.1 hr, but had little effect on subsequent t 1/2s. No effect of MTX on PBC clearance was detected. Our data suggest that in man PBC in concentrations that were high enough to inhibit the renal clearance of MTX failed to alter the clearance of MTX from the CSF when both drugs were administered systemically.

Adult↗

PubMed1978

Cinoxacin: pharmacokinetics and the effect of probenecid.

Cinoxacin is a new synthetic organic antibacterial compound which has a serum half-life of approximately 1 hour. Most of the drug is eliminated in man by the kidney, primarily as unchanged drug. The renal clearance of cinoxacin is slightly greater than the usually accepted value for the average glomerular filtration rate, which suggests that it is probably filtered and is also secreted by the tubule. Results after pretreatment with probenecid further suggest secretion of the drug.

Adult↗

PubMed1978

New spectrophotofluorometric assay for probenecid.

A new spectrophotofluorometric assay for probenecid is presented based on conversion of the drug to a fluorescent anthranilic acid derivative. The assay is especially applicable with "clean" biological fluids such as cerebrospinal fluid and offers severalfold greater sensitivity than the commonly used UV method.

Animals↗

PubMed1986

Probenecid disposition by parallel Michaelis-Menten and dose-dependent pseudo-first-order processes.

Re-evaluation of published data on the urinary excretion of probenecid [4-(dipropylamino)sulfonylbenzoic acid, 1] and its metabolites as a function of orally administered dose has revealed that the elimination process is comprised of five parallel pathways. Excretion of the major metabolite, the acyl glucuronide 2 (35-45% of dose), follows Michaelis-Menten kinetics. The three oxidized metabolites, the mono-N-propyl, carboxylic acid, and secondary alcohol derivatives 3, 4, and 5, respectively, (totaling 30% of dose), each adhere to pseudo-first-order kinetics in which the elimination rate constant, as a result of product inhibition, is a function of the administered dose. Four to 13% of the dose is eliminated unchanged in apparent first-order fashion. A mathematical relationship between elimination half-life and dose, under conditions of product inhibition, is derived. Computer simulation of the elimination process confirms the experimental observation that the fraction of dose excreted in the form of each metabolite remains relatively constant over the dose range of 0.5 to 2 g. This study is believed to represent the first application of parallel Michaelis-Menten and dose-dependent pseudo-first-order processes to drug disposition. It demonstrates that the observation of constant proportions of excreted metabolites over a relatively wide range of doses does not provide evidence that the elimination process remains first-order.

Dose-Response Relationship, Drug↗

PubMed1977

Probenecid in CSF and plasma of rabbits and dogs measured by radioimmunoassay.

Probenecid (P) in CSF of rabbits and dogs was investigated using a new radioimmunoassay technique. In rabbits, under steady-state conditions, CSF/free plasma concentration ratios of P were found to be similar to those reported in man. The ratios were concentration dependent and less than 0.5 suggesting an inhibition of transport of the drug in CNS. Under nonsteady-state conditions, no clear evidence of a transport system was found in dogs.

Animals↗

PubMed1989

Pharmacokinetics of ketoprofen enantiomers in cholecystectomy patients: influence of probenecid.

Ketoprofen (KT), a 2-arylpropionic acid nonsteroidal antiinflammatory drug, is administered as a racemate. Previous reports suggest stereoselective biliary excretion of KT enantiomers. This hypothesis was tested by administering 50 mg racemic KT to five patients who required bile drainage following cholecystectomy surgery. Subsequently, to study the influence of probenecid (PB), an inhibitor of KT renal elimination, on the biliary excretion, 1000 mg PB was administered 1.5 h before KT to the same patients. The unchanged and conjugated (as glucuronides) KT enantiomers were measured in plasma, urine and bile. In general, KT enantiomers had different plasma concentration-time curves. As compared to normal subjects, these patients had comparable AUCs and shorter t1/2s. Biliary concentrations of conjugated S-KT were greater than R-KT. Nevertheless, the total cumulative biliary excretion of conjugated KT did not exceed 2% of the dose ruling out this pathway as a significant route of KT elimination. There was a positive and significant correlation between the cumulative urinary excretion of conjugated KT enantiomers and creatinine clearance. Although PB did not influence the pattern of stereoselectivity of KT, it increased AUC and prolonged t1/2 of the enantiomers. While reducing cumulative urinary excretion, PB increased total biliary elimination of conjugated KT enantiomers. This, however, did not totally compensate for the reduced urinary excretion. It is suggested that the impaired conjugation of KT caused by PB administration may result in the augmentation of other, otherwise minor, metabolic pathways.

Adult↗

PubMed1979

Alteration of plasma ketamine levels in mice by probenecid.

Probenecid increases plasma ketamine levels in mice concurrently with an enhancement of duration of loss of righting reflex. The magnitude of these changes is directly related to the dose of ketamine and intervals between administration of compounds. Plasma levels of anesthetic are similar for all animals upon termination of hypnosis.

Animals↗

PubMed1993

Effect of ascorbic acid, acivicin and probenecid on the nephrotoxicity of 4-aminophenol in the Fischer 344 rat.

4-Aminophenol (p-aminophenol, PAP) causes selective necrosis to the pars recta of the proximal tubule in Fischer 344 rats. The basis for this selective toxicity is not known but PAP can undergo oxidation in a variety of systems to form the 4-aminophenoxy free radical. Oxidation or disproportionation of this radical will form 1,4-benzoquinoneimine which can covalently bind to cellular macromolecules. We have recently reported that a glutathione conjugate of PAP, 4-amino-3-S-glutathionylphenol, is more toxic to the kidney than the parent compound itself. In this study we have examined the distribution and covalent binding of radiolabel from 4-[ring 3H]-aminophenol in the plasma, kidney and liver of rats 24 h after dosing and related these findings to the extent of nephrotoxicity. In addition, we have examined the effect of ascorbic acid which will slow the oxidation of PAP; acivicin, an inhibitor of gamma-glutamyltransferase and hence the processing of glutathione-derived conjugates; and probenecid, an inhibitor of organic anion transport on the nephrotoxicity produced by PAP. Administration of a single dose of PAP at 458 or 687 mumol kg-1 produced a dose-related alteration in renal function within 24 h which was associated with proximal tubular necrosis. The lesion at the lower dose was restricted to the S3 proximal tubules in the medullary rays, while at the higher dose it additionally affected the S3 tubules in the pars recta region of the cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminophenols↗

PubMed1983

Pharmacokinetics of sulbactam and ampicillin following oral administration of sultamicillin with probenecid.

Eight volunteers each received lg of probenecid followed immediately by 1.5 g sultamicillin, both given by the oral route. Plasma concentrations of ampicillin and sulbactam were measured using a differential bioassay method. An ampicillin mean peak plasma concentration of 23.1 mg/l was found typically 1.5 h after dosing; the mean peak plasma concentration of sulbactam (10.0 mg/l) occurred at the same time. The mean plasma half-life of ampicillin was 1.45 h and that of sulbactam 1.3 h. The mean urinary recovery of ampicillin was 65% and that of sulbactam 62%. Five of the volunteers reported minor changes in bowel habits.

Administration, Oral↗

PubMedDate not supplied

Influence of probenecid on the urinary excretion rates of the diastereomeric benoxaprofen glucuronides.

A major biotransformation pathway for many NSAIDs from the group of optically active 2-arylpropionic acids is the conjugation with D-glucuronic acid, forming diastereomers. These conjugates of the S-(+)-and the R-(-)-enantiomers can be separated directly, e.g., by ion-pair chromatography on a C18-column using a mixture of tetrabutylammonium buffer pH 2.5 and acetonitrile as mobile phase. In man about 40% of the dose was recovered in urine as glucuronides (ratio S:R = 2.2) within 96 hours of p.o. administration of racemic drug. When probenecid, which is known to influence the elimination of several acidic drugs, was administered in addition, the amount excreted as glucuronides during 4 days was clearly reduced. Furthermore, the enantiomeric ratio was changed significantly, possibly because of an increase of stereoinversion due to the reduced drug clearance.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1988

Inhibition of purine catabolism by benzbromarone in isolated rat liver cells. Comparison with allopurinol and probenecid.

Benzbromarone, a potent uricosuric agent, inhibited allantoin production in isolated hepatocytes at concentrations half to ten times greater than therapeutic plasma levels of the drug. In addition, the drug at these concentrations also markedly inhibited xanthine oxidase (EC 1.2.1.37), an enzyme involved in the regulation of this pathway. We found that allopurinol is several times superior to benzbromarone in the lowering of allantoin production (if they are compared in terms of their relative therapeutic levels), and that probenecid had no effect on it.

Allopurinol↗