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At least 19 recordsLinked to original sources
PubMed1986

Pharmacokinetics of probenecid and the effect of oral probenecid administration on the pharmacokinetics of cefazolin in mares.

The pharmacokinetics and bioavailability of probenecid given IV and orally at the dosage level of 10 mg/kg of body weight to mares were investigated. Probenecid given IV was characterized by a rapid disposition phase with a mean half-life of 14.0 minutes and a subsequent slower elimination phase with a mean half-life of 87.8 minutes in 5 of 6 mares. In the remaining mare, a rapid disposition phase was not observed, and the half-life of the elimination phase was slower (172 minutes). The mean residence time of probenecid averaged 116 minutes for all 6 mares and 89.2 minutes for the 5 mares with biphasic disposition. The total plasma clearance of probenecid averaged 1.18 +/- 0.49 ml/min/kg, whereas renal clearance accounted for 42.6 +/- 9.3% of the total clearance. The steady-state volume of distribution of probenecid averaged 116 +/- 28.2 ml/kg. Plasma protein binding of probenecid was extensive, with 99.9% of the drug bound at plasma probenecid concentrations of 10 micrograms/ml. The maximum plasma probenecid concentration after 10 mg/kg orally averaged nearly 30 micrograms/ml. The half-life of probenecid after oral administration was approximately 120 minutes. Oral bioavailability was good with greater than 90% of the dose absorbed. The effect of probenecid on tubular secretion of organic anions was evaluated by determining the pharmacokinetics of IV cefazolin (11 mg/kg) administered alone and 15 minutes after probenecid (10 mg/kg orally). Treatment with probenecid did not affect pharmacokinetic values of cefazolin. This failure of probenecid to alter the pharmacokinetics of cefazolin may be caused by insufficient plasma probenecid concentrations after the oral dose.

Administration, Oral↗
PubMed1994

Should probenecid be used to reduce the dicloxacillin dosage in orthopaedic infections? A study of the dicloxacillin-saving effect of probenecid.

Reduction in the dosage of dicloxacillin from 500 mg to 250 mg 3 times a day would mean lowering of costs and less side-effects in orthopaedic infections. In this cross-over study, the serum concentrations of dicloxacillin were measured in 9 patients after administration of dicloxacillin 500 mg 3 times a day (dicloxacillin 500 mg) and after co-administration of 250 mg dicloxacillin and 250 mg probenecid 3 times per day (dicloxacillin 250 mg+probenecid 250 mg). Concentrations were measured every hour after the tablet intake. The mean maximum serum concentrations of dicloxacillin were 17.1 micrograms/ml (dicloxacillin 500 mg) and 12.2 micrograms/ml (dicloxacillin 250 mg+probenecid 250 mg), respectively (P < 0.05). Serum concentrations above 3 micrograms/ml were obtained during 285 min. in both regimes, but the individual variations were biggest during in the dicloxacillin 250 mg+probenecid 250 mg treatment. Serum concentrations above 5 micrograms/ml were in mean measured during 228 min. (dicloxacillin 500 mg) and 190 min. (dicloxacillin 250 mg+probenecid 250 mg), respectively (P < 0.05). The clinical significance of these findings is being discussed. In theory, treatment with dicloxacillin 250 mg+probenecid 250 mg may be as sufficient as dicloxacillin 500 mg.

Administration, Oral↗
PubMed1976

Intravenous probenecid loading. Effects on plasma and cerebrospinal fluid probenecid levels and on monoamine metabolites in cerebrospinal fluid.

Probenecid blocks the active transport from cerebrospinal fluid to blood of homovanillic acid and 5-hydroxyindoleacetic acid, thus increasing cerebrospinal fluid levels of these products of central monoamine metabolism. The half-life in plasma of probenecid given as a single intravenous infusion (40 mg per kilogram of body weight) to patients with either Huntington's chorea or Parkinson's disease averaged about 6.6 hours. In cerebrospinal fluid, peak values for homovanillic acid and 5-hydroxyindoleactic acid occurred in samples collected 8 hours after the 1-hour probenecid infusion was started. Even after 4 hours, however, levels of both monoamine metabolites were significantly increased. There was a positive correlation between cerebrospinal fluid levels of probenecid and the increase in 5-hydroxyindoleacetic acid but not homovanillic acid. Compared with the oral administration of probenecid, the intravenous infusion technique produced more consistent elevations in plasma and cerebrospinal fluid probenecid levels, greater increases in cerebrospinal fluid homovanillic acid values, and fewer gastrointestinal side effects.

Administration, Oral↗
PubMedDate not supplied

Comparison of ampicillin plus probenecid with amoxicillin plus probenecid for treatment of uncomplicated gonorrhea.

The efficacy of 3 g of amoxicillin plus 1 g of probenecid was compared with the efficacy of 3.5 g of ampicillin plus 1 g of probenecid for the treatment of uncomplicated gonorrhea. In a clinical trial no therapeutic failure was seen among 60 patients who were treated with the former regimen. The combination of ampicillin plus probenecid resulted in two therapeutic failures (3.6%) among the 55 patients given it. It was concluded that amoxicillin plus probenecid is as effective as ampicillin plus probenecid for the treatment of uncomplicated gonorrhea.

Adolescent↗
PubMed1978

Talampicillin and probenecid compared with ampicillin and probenecid for the treatment of gonococcal urethritis in men.

Two hundred and ten men suffering from uncomplicated gonococcal urethritis were treated with one of two treatment schedules. Of 109 patients treated with 3 g ampicillin and 2 g probenecid (group A) there were two recurrences in the first week after treatment and none in the second week. Of 101 patients treated with 1.5 g talampicillin and 2 g probenecid (group B), there were three recurrences in the first week and none in the second week. Both antibiotics were well tolerated, but one patient vomited two hours after taking talampicillin. The sensitivity pattern of Neisseria gonorrhoeae to penicillin at The London Hospital has shown an increase in the proportion of more sensitive strains during the last three years. Talampicillin given in a single dose with probenecid is satisfactory in the treatment of acute gonococcal urethritis but, apart from the smaller dosage, it does not offer any advantage over ampicillin with probenecid.

Adolescent↗
PubMed1975

Serum concentrations of ampicillin and probenecid and ampicillin excretion after repeated oral administration of a pivampicillin-probenecid salt (MK-356).

Twenty male volunteers received oral doses (2100, 1050, and 525 mg) of a pivampicillin-probenecid salt in a 1 to 1 molar ratio (MK-356) at 12 hour intervals. After each dose peak serum concentrations of probenecid were observed 2 hours later than peak concentrations of ampicillin. Following the first dose of MK-356 the apparent elimination rate of ampicillin was dose-dependent and did not follow first order kinetics, as it showed a longer apparent half life after a higher dose. An equal dose of MK-356 administered 12 hours later caused an increase in the peak serum ampicillin level greater than expected from the concentration of ampicillin after the preceding dose. In twelve male volunteers who received at random 525 mg of MK-356 or 350 mg of pivampicillin, each three times daily for 4 days, the areas under the ampicillin concentration curve were the same after the first or last dose of either drug. When 2100 or 1050 mg of MK-356 was taken as an initial dose, 30 to 40 per cent of the ampicillin was recovered from urine in the ensuing 12 hours. The results indicate that when at least 400 mg probenecid was coadministered twice daily with 700 mg pivampicillin (MK-356), the peak serum concentrations of ampicillin were increased and its elimination rate slowed following successive doses.

Administration, Oral↗
PubMed1984

Liquid chromatographic determination of homovanillic acid, 5-hydroxyindoleacetic acid and probenecid levels in human cerebrospinal fluid during probenecid test.

Homovanillic acid and 5-hydroxyindoleacetic acid, respectively the major metabolites of the central neurotransmitters dopamine and serotonin, are present in human lumbar cerebrospinal fluid, and their determination during the probenecid test is used to study brain monoamine abnormalities in man. We developed a high performance liquid chromatographic technique coupled with electrochemical detection which allows the simultaneous determination of homovanillic acid and 5-hydroxyindoleacetic acid on 10 microliter of human lumbar cerebrospinal fluid. Another liquid chromatographic technique coupled with ultra-violet detection was applied to the measurement of probenecid after injection of 10 microliter of native cerebrospinal fluid. The main advantages of these two techniques are their simplicity, sensitivity, rapidity (five cerebrospinal fluid samples are analysed within one hour) and their good day-to-day reproducibility . These methods were applied to probenecid tests performed in several neurological patients.

Adolescent↗
PubMed1975

Ampicillin plus probenecid compared with procaine penicillin plus probenecid in the treatment of gonorrhoea.

396 male patients with gonococcal urethritis were treated by one of three treatment schedules. Of 132 patients treated with 2.4 m.u. procaine penicillin plus 2 g. probenecid, 109 were followed. There were three (2.8 per cent) recurrences in the first week and none in the second. Of 132 patients treated with 2 g. ampicillin plus 2 g. probenecid, 112 were followed. There were four (3.6 per cent.) recurrences in the first week and three (2.6 per cent.) in the second (total of 6.2 per cent.). Of 132 patients treated with 3 g. ampicillin plus 2 g. probenecid, 115 were followed. There was one (0.8 per cent.) recurrence in the first week and five (4.4 per cent.) in the second (total of 5.2 per cent.). A close correlation was found between the sensitivities of gonococcal strains to ampicillin and to penicillin. The overall sensitivity pattern of N. gonorrhoeae to penicillin had not changed at The London Hospital since the last report in 1972, but there was further evidence of cross-resistance between penicillin and cotrimoxazole.

Adolescent↗
PubMed1976

[Treatment of female gonorrhea. Therapeutic results with pivampicillin-probenecid and penicillin procaine-probenecid combinations].

A controlled trial of the relative efficacies of procaine penicillin G and pivampicillin for single dose treatment of uncomplicated gonorrhea in female was performed. Confirmation of the disease was obtained by bacteriological isolation of Neisseria gonorrhea from uretral, cervical or rectal exudates inoculated in suitable media. Based upon their previous experience, the authors used probenecid, along with both antibiotics, as a way of increasing the effectiveness of these drugs. Twentynine patients received probenecid 1 g. followed by oral pivampicillin, in a single dose of 1,4 g. Therapeutical results were evaluated in twenty-four, with clinical and bacteriological cure of eighteen. The other group included fifty-two patients treated with probenecid 1 g. followed by a single intramuscular dose of 3.000.000 U. of procaine penicillin G. The therapeutical results in the last group were evaluated in forty patients, with clinical and bacteriological cure of thirty-three. According to the above mentioned results procaine penicillin G seems to offer a slightly superior probability of cure.

Adolescent↗
PubMed1991

Rapid high-performance liquid chromatographic assay for the simultaneous determination of probenecid and its glucuronide in urine. Irreversible binding of probenecid to serum albumin.

A reversed-phase high-performance liquid chromatographic (HPLC) assay for the simultaneous determination of probenecid and its glucuronide in urine has been developed. The genuine glucuronide conjugate was isolated from urine by the use of solid-phase extraction on Amberlite XAD-2 and finally purified by the use of preparative HPLC on a Sepharon Hema 1000 RP-18 column. The purity of the product obtained was 88.9%. The isolated glucuronide was used as a standard sample. Of a p.o. dose of 500 mg to two volunteers, 26 and 29% were excreted as the ester glucuronide, while 1.0 and 2.7% were excreted unmetabolized. The stability of the ester glucuronide was investigated in aqueous buffers, buffered urine and human serum albumin solutions. The glucuronide was unstable in neutral and mildly alkaline solutions, and special precautions have to be taken during sampling and sample treatment in order to preserve the genuine glucuronide. The presence of human serum albumin in the solution stabilized the glucuronide against isomerization/rearrangements but catalysed the hydrolysis of the glucuronide. When incubating human serum albumin with the ester glucuronide, probenecid was shown to be covalently bound to the protein probably via a transacylation reaction.

Chromatography, High Pressure Liquid↗
PubMed1993

Ketoprofen-probenecid interaction in the rat: a probenecid concentration-dependent stereoselective process.

Probenecid (PB) is believed to interact with the chiral nonsteroidal anti-inflammatory drug ketoprofen (KT) through competition for glucuronide conjugation and subsequent renal and/or biliary excretion of formed KT conjugates. It is unknown whether the interaction is dependent on PB concentration and whether both KT enantiomers are affected to the same extent. We measured intact and conjugated R-KT, S-KT, and PB in the plasma and urine of female Sprague-Dawley rats after intravenous doses of 10 mg of racemic KT per kg and 0, 25, 50, 100, 150, 175, and 200 mg of PB per kg. Elevated levels of both enantiomers were observed, with S-KT being affected to a much greater extent. Significant positive correlations were found between the concentrations in plasma of KT enantiomers and PB at various sampling times, with the strongest correlations being found at 2 h for R-KT (r = 0.708) and 1.5 h for S-KT (r = 0.913). The areas under the concentration-time curve (AUC) from 0-24 h for R-KT (r = 0.697) and S-KT (r = 0.848) also showed strong correlation with AUC of PB. Our data show that as the dose of PB was increased (0-200 mg/kg), the mean S-KT/R-KT ratios for both the AUC and the fraction of the dose excreted as enantiomer conjugates in urine over 24 h increased progressively from 12.1 +/- 2.3 to 27.6 +/- 5.0 and from 6.8 +/- 0.7 to 36.4 +/- 12.2, respectively. These findings clearly demonstrate that the KT-PB interaction in the rat is a PB concentration-dependent process.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Effect of probenecid on the renal and nonrenal clearances of zidovudine and its distribution into cerebrospinal fluid in the rabbit.

The effect of probenecid on the renal excretion of zidovudine (3'-azido-3'-deoxythymidine; AZT) and its distribution into CSF was studied in the rabbit. Although probenecid is chemically unrelated to AZT, it has been shown that probenecid inhibits AZT elimination in Acquired Immunodeficiency Syndrome (AIDS) patients. The effect of probenecid on the renal clearance of AZT after an iv bolus dose was studied in crossover experiments in the absence (control) and the presence of a continuous iv infusion of probenecid. Probenecid coadministration increased the AZT plasma AUC by 70%, by proportionally decreasing the total body clearance. The renal clearance decreased by 50%. The effect of probenecid on the renal clearance of AZT at steady state was studied by measuring the renal clearance of AZT at different steady-state plasma probenecid concentrations. The renal clearance of AZT decreased with increasing probenecid concentration, suggesting competitive inhibition of the secretion of AZT in the renal tubule. The relationship between AZT renal clearance and probenecid plasma concentrations, during and after probenecid iv infusion in conscious and in anesthetized uretercannulated rabbits, showed hysteresis, indicating that probenecid plasma concentration is different from the concentration at the site of interaction. This suggests the presence of an effect compartment for the inhibition of AZT renal excretion by probenecid. The effect of probenecid on the CSF distribution of AZT was also studied in the rabbit. Probenecid coadministration caused a sevenfold increase in the AZT AUCCSF in probenecid-treated rabbits when compared with controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Protein binding as a component of drug interaction in cellular pharmacokinetic studies. Effects of probenecid on transport and accumulation of methotrexate in Ehrlich ascites tumor cells in vitro.

The organic acid probenecid has been shown to interfere with the active extrusion of methotrexate (MTX) from L1210 tumor cells in vitro leading to enhanced MTX accumulation and increased formation of MTX polyglutamate derivatives. In the presence of serum albumin (4 g/100 ml), to which probenecid is bound, the inhibition by probenecid of [3H]MTX efflux from the Ehrlich ascites tumor cell was reduced markedly. While half-maximal inhibition of MTX efflux occurred with 0.12 mM probenecid in the absence of albumin, 1.45 mM probenecid was required in its presence. The presence of albumin also modified the probenecid-induced elevation of steady-state MTX levels in the tumor cell. Maximal elevation of cellular MTX levels occurred with 0.5 mM probenecid in the absence of albumin, and 3 mM probenecid in its presence. Serum albumin further reversed the effects of probenecid on MTX influx. While probenecid inhibited influx of 1 microM [3H]MTX in the absence of albumin (half-maximal inhibition at approximately 1 mM probenecid), probenecid stimulated MTX influx in its presence (half-maximal effect at 0.5 to 1 mM). Equilibrium dialysis studies demonstrated that probenecid displaced MTX from albumin, increasing the effective free concentration of MTX in the incubation medium, and hence the rate of MTX influx. Therefore, probenecid may enhance the accumulation of MTX in the tumor cells by increasing the level of free (as opposed to albumin bound) MTX in the extracellular medium as well as by direct inhibition of MTX efflux. These observations may provide an additional explanation for probenecid enhancement of the therapeutic efficacy of MTX in tumor bearing mice and highlight the importance of assessing drug-protein interactions in an in vitro experimental model.

Animals↗
PubMed1993

Cephalosporin-probenecid drug interactions.

The effect of concurrent probenecid administration on the pharmacokinetics of cephalosporin antibiotics varies with the available cephalosporins. Most cephalosporins are affected to some degree by concurrent probenecid administration, although ceforanide, ceftazidime, ceftriaxone and latamoxef (moxalactam) have no significant changes in pharmacokinetics. For those cephalosporins affected by probenecid, the predominant findings are impairment in renal clearance resulting in increased peak serum concentrations, an increased area under the concentration-time curve (AUC), and both delayed and prolonged recovery of the cephalosporin in the urine. The distribution of the cephalosporins is affected to varying degrees, with reports of increased penetration into ocular, central nervous system and blister fluids noted with some agents. The clinical relevance of the changes in cephalosporin distribution associated with probenecid administration has not been investigated. The dose and timing of probenecid administration appear to be major determinants in any possible interaction. Studies with ceftizoxime and cefoxitin suggest that larger probenecid doses result in greater changes in the pharmacokinetics of cephalosporins. Prolonged probenecid therapy before administration of a cephalosporin did not seem to be as relevant as the probenecid dosage in determining the magnitude of the interaction. Probenecid administration with or immediately before cephalosporin administration appears able to produce these documented changes in cephalosporin pharmacokinetics. The route of administration (oral versus parenteral) of either prolosporin pharmacokinetics. The route of administration (oral versus parenteral) of either probenecid or the cephalosporin does not appear to influence the characteristics of the interactions. The therapeutic efficacy of a combination of a cephalosporin with probenecid has been most thoroughly studied for single-dose treatment of gonorrhoea. The addition of probenecid to cephalosporin therapy results in sustained systemic concentrations adequate for eradication of Neisseria gonorrhoeae. Regimens involving either second or third generation cephalosporins demonstrate good success rates with single-dose therapy. However, the success of ceftriaxone administered alone for treatment of both penicillase-producing and non-penicillase-producing strains of N. gonorrhoeae suggests that the addition of probenecid is unnecessary. The use of probenecid, in combination with cephalosporins, to enhance the treatment of other venereal and systemic infections has preliminary, inconclusive support.

Cephalosporins↗