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At least 19 recordsLinked to original sources

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↗

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↗

PubMed1992

Competitive inhibition of zidovudine clearance by probenecid during continuous coadministration.

The pharmacokinetics of zidovudine in the rabbit were studied during coadministration of probenecid at two infusion rates. Each animal (n = 6) served as its own control during an initial 8-hr infusion of zidovudine. In the second 8-hr infusion period, probenecid was coadministered with zidovudine. Urine samples were collected by bladder flush hourly for 19 hr. Plasma samples were taken at the midpoint of the urine collection interval and at predetermined intervals for 3 hr postinfusion. Plasma concentrations of zidovudine reached steady state during control periods but showed incomplete attainment of steady state during the infusions of probenecid at the higher rate. Total and renal clearance of zidovudine were reduced by 24.0 +/- 4.0 and 20.7 +/- 15%, respectively, during low-dose probenecid treatment and 48.9 +/- 7.4 and 55.7 +/- 3.4%, respectively, with high-dose probenecid treatment. Plasma probenecid concentrations during low-dose and high-dose infusion were 56.9 +/- 12 and 248 +/- 42 micrograms/ml. Postinfusion data showed that the zidovudine terminal half-life during high-dose probenecid treatment was longer than that with low-dose probenecid treatment (58.2 +/- 4.6 vs 39.0 +/- 9.1 min). The volume of distribution of zidovudine also decreased (1.76 +/- 0.27 vs. 1.10 +/- 0.095 L/kg) as a result of probenecid coadministration. The results are consistent with competitive inhibition of renal and nonrenal clearances. A drug interaction model relating zidovudine clearances to plasma probenecid concentrations was derived. Michaelis-type constants for probenecid inhibition of zidovudine renal and nonrenal clearances were 73 and 55 micrograms/ml, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1977

Inhibition of probenecid uricosuria by pyrazinamide and para-aminohippurate.

Both para-aminohippurate (PAH) and pyrazinamide inhibited the uricosuric response to probenecid administration. The mechanism of this inhibition of probenecid uricosuria was assessed in 18 male subjects. The decrease in uricosuria was assessed in 18 male subjects. The decrease in uricosuric response to probenecid observed after pyrazinamide administration or PAH infusion occurs by different mechanisms. Administration of PAH and probenecid together resulted in reduced excretion of both drugs. PAH was weakly uricosuric and did not appear to inhibit urate secretion. PAH inhibition of probenecid uricosuria is accounted for by inhibition of probenecid secretion. Probenecid excretion was not affected by pyrazinamide administration. Inhibition of probenecid-induced uricosuria by pyrazinamide is most likely due to inhibition of urate secretion. The urate secretory carrier inhibited by pyrazinamide appears to be independent of that responsible for secretion of probenecid and PAH. Probenecid secretion appears to be required for its uricosuric effect.

Adolescent↗

PubMed1992

Pharmacokinetics and the effect of probenecid on the renal excretion mechanism of diprophylline.

The mechanism of renal excretion of diprophylline (DPP) and the effect of probenecid on the active transport of DPP in renal tubules were investigated in rats. The concentration of DPP in plasma increased in proportion to the doses of 10, 30, and 60 mg/kg. The pharmacokinetic parameters and the urinary excretion of DPP did not change significantly with the dose. These findings indicate that DPP possesses dose-independent pharmacokinetics. Pharmacokinetic parameters for tubular secretion of DPP, as determined by a single-injection renal clearance method, were 21.25 micrograms/mL for the Michaelis-Menten constant and 102.38 micrograms/min for maximum velocity. Coadministration of probenecid decreased the total body clearance of DPP but did not change in the steady-state volume of distribution of DPP. The effect of probenecid concentration on the steady-state renal clearance of DPP was evaluated by continuously infusing probenecid at various rates. The renal clearance of DPP decreased as the probenecid concentration increased, a result indicating that probenecid inhibits the tubular secretion of DPP. However, probenecid did not inhibit the renal secretion of DPP completely, probably because of the existence of probenecid-insensitive transport systems for DPP in the renal proximal tubule. The Michaelis-Menten constant, maximum velocity, and glomerular filtration rate, as calculated with the competitive inhibition model for renal clearance of DPP, correlated well with estimated values after a single intravenous administration, as described earlier. The competitive inhibition constant of probenecid was 15.86 micrograms/mL.

Animals↗

PubMed1992

Capacity-limited renal glucuronidation of probenecid by humans. A pilot Vmax-finding study.

Probenecid shows dose-dependent pharmacokinetics. When in one volunteer the dose is increased from 250 to 1,500 mg orally, the t1/2 increased from 3 to 6 h. The Cmax was 14 micrograms/ml with a dosage of 250 mg, 31 micrograms/ml with 500 mg, 70 micrograms/ml with 1,000 mg and 120 micrograms/ml with 1,500 mg. The tmax remained 1 h for all four dosages. The AUC/dose ratio increased with the dose, indicating nonlinear elimination. The total body clearance declined from 64.5 ml/min for 250 mg to 26.0 ml/min for 1,500 mg. The renal clearance of probenecid remained constant, 0.6-0.8 ml/min. Protein binding of probenecid is high (91%) and independent of the dose. The phase I metabolites show lower protein binding values (34-59%). The protein binding of probenecid glucuronide in vitro (spiked plasma) is 75%. Probenecid is metabolized by cytochrome P-450 to three phase I metabolites. Each of the metabolites accounts for less than 10% of the dose administered; the percentage recovered in the urine is independent of the dose. The main metabolite probenecid glucuronide is only present in urine and not in plasma. The renal excretion rate--time profile of probenecid glucuronide shows a plateau value of approximately 700 micrograms/min (46 mg/h) with acidic urine pH. The duration of this plateau value depends on the dose: 2 h at 500 mg, 10 h at 1,000 mg and 20 h at 1,500 mg. It is demonstrated that probenecid glucuronide must be formed in the kidney during its passage of the tubule. The plateau value in the renal excretion rate of probenecid value reflects its Vmax of formation.

Adult↗

PubMed1979

Probenecid-induced increase of 5-hydroxytryptamine synthesis in rat brain, as measured by formation of 5-hydroxytryptophan.

Probenecid blocks the efflux of 5-hydroxyindole acetic acid (5-HIAA) from the central nervous system, and has therefore been used for turnover measurements of central 5-hydroxytryptamine (5-HT). This substance also elevates tryptophan (TP) levels in rat brain. In this investigation, the time courses of probenecid and TP levels in rat serum and brain after administration of probenecid were studied. Maximal levels of probenecid were reached within 15 min, followed by 50% decrease of serum TP and a 40% increase of brain TP. Brain levels of probenecid were about ten times lower than those in serum. Because TP level in brain is an important factor in the control of cerebral 5-HT synthesis, the effects of probenecid on 5-HT formation in rat brain were investigated. By means of the aromatic L-amino acid decarboxylase inhibitors Ro 4-4602 and NSD 1015, an enhancement of TP hydroxylation of about 35% was demonstrated. It was concluded that penetration of probenecid into the brain is very limited and that probenecid, in addition to blocking egress of 5-HIAA from the CNS, stimulates 5-HT synthesis.

5-Hydroxytryptophan↗

PubMed1992

Direct measurement of probenecid and its glucuronide conjugate by means of high pressure liquid chromatography in plasma and urine of humans.

Probenecid with its phase-I metabolites, and phase-II glucuronide conjugate can be analysed by a gradient high pressure liquid chromatographic method. Probenecid glucuronide in plasma with pH 7.4 is not stable and declines to 10% of the original value within 6 h (t1/2 approximately 1 h). Probenecid glucuronide is stable in urine with pH 5.0, moderately unstable at pH 6.0 (t1/2 approximately 10 h), and unstable at pH 8.0 (t1/2 approximately 0.5 h). Probenecid glucuronide is stable in water and 0.01 mol/l phosphoric acid in the autosampler of the high pressure liquid chromatograph. The decrease in concentration in water is 5.5% during 9 h and 0% in diluted acid. Probenecid glucuronide and the phase-I metabolites were not detectable in plasma. The main compound in fresh urine is the phase-II conjugate probenecid glucuronide (62% of a 500 mg dose); the phase-I metabolites are present and only a trace of probenecid is present. The percentage of the dose of the phase-I metabolites varies between 5 and 10, while hardly any probenecid is excreted unchanged (0.33%).

Chromatography, High Pressure Liquid↗

PubMed1977

Comparison of methods for determining probenecid in tablets and flavored oral suspensions containing ampicillin.

Several methods for quantitating probenecid were compared: USP XIX method for probenecid in tablets, a modified USP extraction method for probenecid in tablets, a new column extraction method for probenecid in tablets and oral suspensions containing ampicillin, and a high pressure liquid chromatographic (HPLC) method for probenecid in tablets and oral suspensions containing antibiotics. The first 3 methods were satisfactory for probenecid in bulks and tablets but proved unsatisfactory for oral suspeonsions containing flavors. The flavors gave positive interference for probenecid in oral suspensions. The HPLC method, although more time-consuming, separated probenecid from excipients, thus eliminating positive interference from flavors.

Ampicillin↗

PubMed1978

Effects of probenecid on furosemide response.

Furosemide gains access to its intraluminal site of action by active secretion by the organic acid transport system of the proximal tubule. Inhibition of this transport by probenecid would predictably decrease the effect of furosemide. In this study in 8 normal volunteers, however, the opposite occurred; namely, pretreatment with probenecid increased the overall response to furosemide by prolonging its effect. Sodium excretion in 8 hr due to 40 mg of furosemide rose from 262 +/- 16 to 358 +/- 11 mEq after probenecid. Urine volume increased from 3,265 +/- 275 to 4,165 +/- 183 ml after probenecid. Analysis of the time-course of the increased diuresis and natriuresis showed that probenecid actually decreased the response for the first 60 to 90 min after furosemide but increased the subsequent response sufficiently to result in a greater overall effect. Possible explanations include access of furosemide to its active site from the serum, an effect of probenecid on prostaglandin transport, and a changing pharmacokinetic interaction between probenecid and furosemide.

Adult↗

PubMed1975

Probenecid: dosage, levels in plasma and cerebrospinal fluid (CSF) and influence upon CSF levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the rabbit.

Probenecid retards the efflux of acid monoamine metabolites from the brain tissue and CSF to the blood. The probenecid-induced accumulation of these metabolites is held to be indicative of the turnover rate of the corresponding amines. Although the penetration of probenecid into the CSF does not proceed at a constant rate, Korf et al. (1972) and Sjöstrom (1972) have shown a correlation between CSF levels of probenecid and that of HVA and 5-HIAA. In this study an attempt was made to establish the relationship between doses of probenecid and levels of this compound in plasma and CSF; between levels in plasma and CSF; and between CSF levels of probenecid and of HVA and 5-HIAA. This study was performed in a homogeneous group of laboratory rabbits. All correlations proved to be significant. The implications of these results for studies using the probenecid technique are discussed.

Animals↗

PubMed1976

Increased rate of disappearance of serum probenecid in barbital dependent rats.

Rats were made barbital dependent by administration of barbital in their drinking water. Subsequently, the rats were either not withdrawn (BN) or withdrawn from barbital for 24 h (BW-24). Before sacrifice, probenecid was administered to measure brain serotonin turnover. A statistically significant decrease in 5-hydroxyindoleacetic acid (5-HIAA) accumulation was observed in the cerebral cortex medulla pons and midbrain. Subsequentialy, serum levels of probenecid were also measured by gas chromatography to determine if chronic barbital consumption might affect circulating probenecid. By ninety minutes following probenecid administration, serum probenecid levels in BN and BW-24 rats were significantly lower than control while a probenecid metabolite was significantly increased. The significantly reduced accumulation of 5-HIAA in brain areas of BN and BW-24 rats is probably the result of the more rapid decline of probenecid rather than a true decrease in serotonin turnover.

Animals↗

PubMed1977

Characteristics of accumulation of probenecid by rabbit kidney cortical slices.

Probenecid was accumulated by renal tissue both under aerobic and anaerobic conditions. The aerobic uptake at a low medium concentration of probenecid was enhanced three- or fourfold by acetate, while metabolic inhibitors and organic anions like p-aminohippurate (PAH), phenol red, and other substituted phenolsulphonphthalein (PSP) dyes which undergo secretion had an inhibitory effect. Octanoate and succinate stimulated aerobic probenecid uptake at low medium concentrations, but inhibited transport of the drug at high levels. Studies on renal homogenates showed that the anaerobic uptake of probenecid is due to binding to tissue constituents. Binding characteristics of PSP dyes to phospholipid vesicles and a representative binding protein, human serum albumin, exhibited close similarity to that of binding to renal tissue. Hydrophobic compounds like octanoate and PSP dyes partially inhibited probenecid binding. In contrast, transport of probenecid was almost completely abolished by these substances and PAH at high medium concentrations. On the basis of the results presented in this paper, it is concluded that renal transport of probenecid occurs by the common organic anion transport system.

Acetates↗

PubMed1992

Effect of probenecid on tetraethyl ammonium (TEA) transport across basolateral membrane of rabbit proximal tubule.

The effect of probenecid on the transport of tetraethylammonium (TEA) was investigated in rabbit reanal cortical slices in an attempt to ascertain the interaction of organic anion with the organic cation transport system in proximal tubule. Probenecid reversibly inhibited TEA uptake by cortical slices in a dose-dependent manner over the concentration range of 1 and 5 mM. The efflux of TEA was not affected by the presence of 3 mM probenecid. Kinetic analysis indicated that probenecid decreased Vmax without a significant change in Km. Probenecid inhibited significantly tissue oxygen consumption at concentrations of 3 and 5 mM. However, probenecid did not significantly reduce TEA uptake in brush border and basolateral membrane vesicles prepared from renal cortex even at higher concentration of 10 mM. These results indicate that probenecid reduces TEA uptake in cortical slices by inhibiting the tissue metabolism rather than by the interaction with the organic cation transporter.

Animals↗