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PubMedDate not supplied

Probenecid-impaired biliary excretion of acetaminophen glucuronide and sulfate in the rat.

Acetaminophen (APAP; 100 mg/kg iv) and probenecid (50 mg/kg bolus + 11.4 mg/hr/kg infusion) were administered to male Sprague-Dawley rats to examine the disposition of APAP, and its glucuronide (AG) and sulfate (AS) conjugates in plasma, bile, and urine. Probenecid significantly decreased the formation clearance of AG from 3.65 +/- 0.434 to 1.94 +/- 0.441 ml/min/kg and the renal clearance of AS from 9.32 +/- 2.26 to 3.15 +/- 1.21 ml/min/kg. The biliary excretion of AG was reduced approximately 3- to 4-fold by probenecid, from 6.54 to 1.87% of the APAP dose, and the AG biliary excretion rate was decreased 4- to 5-fold during probenecid treatment. The more extensive impairment of AG biliary excretion relative to AG formation suggests that probenecid may inhibit the hepatobiliary transport of AG. The significant reduction in the biliary excretion rate at early time points for AS suggests that probenecid may inhibit hepatic AS transport. The study results indicate that probenecid impairs AG and AS formation, AS renal secretion, and AG and AS biliary excretion.

Acetaminophen↗
PubMed1992

Effect of probenecid on the pharmacokinetics of flunixin meglumine and phenylbutazone in healthy mares.

Pharmacokinetic values for flunixin meglumine (1 mg/kg of body weight) and phenylbutazone (4 mg/kg) dosages were determined after a single IV injection with and without concurrent intragastric administration of probenecid (50 mg/kg) in 6 healthy mares. Significant difference was not apparent in the pharmacokinetic values of flunixin meglumine with and without concurrent probenecid administration. Significant (P less than or equal to 0.05) increase was evident in the 12-hour mean concentration of phenylbutazone (11.45 +/- 1.66 micrograms/ml without probenecid; 14.56 +/- 1.20 micrograms/ml with probenecid) along with significant (P less than or equal to 0.05) reduction in its volume of distribution at steady state associated with concurrent probenecid administration (218.6 +/- 11.52 ml/kg without probenecid; 169.4 +/- 9.25 ml/kg with probenecid).

Animals↗
PubMed1991

Effect of probenecid on phagocytosis and intracellular killing of Staphylococcus aureus and Escherichia coli by human monocytes and granulocytes.

The present study concerns the effects of probenecid on the phagocytosis and intracellular killing of Staphylococcus aureus and Escherichia coli by human monocytes and granulocytes. In both monocytes and granulocytes the inhibitory effect on phagocytosis was very small. Inhibition of intracellular killing of S. aureus by monocytes and granulocytes by probenecid was concentration dependent, being half-maximal at about 2 mM probenecid, and near-maximal at about 5 mM probenecid. The intracellular killing could also be inhibited when probenecid was added when this process was already started. Probenecid also inhibited the intracellular killing of E. coli by granulocytes, but not by monocytes. In the concentration range used, probenecid had no toxic effect on phagocytes or bacteria during the 2 hr of the experiments.

Dose-Response Relationship, Drug↗
PubMedDate not supplied

Effects of probenecid on blood levels and tissue distribution of ampicillin in fowls and turkeys.

The effect of probenecid (a benzoic acid derivative which competitively inhibits active secretion of weak organic acids by the renal tubules) on serum ampicillin concentrations and the distribution of ampicillin in body organs was examined in fowls and turkeys. An aqueous solution of probenecid coadministered intramuscularly, at 200 mg/kg, with sodium ampicillin solution, at 25 mg/kg, resulted in peak serum antibiotic concentration of 16.5 microgram/ml. A similar dose of ampicillin administered alone produced a peak level of 4.6 microgram/ml. Subcutaneous injections of sodium ampicillin at 25 mg/kg with aqueous probenecid at 200 mg/kg resulted in a peak serum ampicillin concentration (12.8 microgram/ml) three times as high as the peak produced by the subcutaneous injection of ampicillin alone at 50 mg/kg (4.2 microgram/ml). The elimination half-life (t 1/2) of the drug (30 min) was increased to 1.5 hr by coadministration of probenecid parenterally, and serum antibiotic levels greater than or equal to 5.0 microgram/ml were maintained during 3 hours. Ampicillin seemed to be poorly absorbed from the gastrointestinal tract of fowls. A single oral bolus administration of ampicillin trihydrate aqueous suspension produced a peak of 0.6 microgram/ml, and coadministrations of aqueous probenecid suspension at 20, 50, and 100 mg/kg respectively produced peaks of 0.9, 1.25, and 1.5 microgram/ml. During 4 and 5 days, when ampicillin was added to the drinking water at rates of 200 and 50 mg/liter, serum ampicillin levels were rather low (peaks of 0.20 and 0.12 microgram/ml, respectively), and although these levels were increased by 50% with the coadministration of probenecid they were considered to be of limited clinical value for treating systemic bacterial infections. Probenecid did not change the distribution of ampicillin in the organs.

Administration, Oral↗
PubMed1984

Probenecid reduces cochlear effects and perilymph penetration of furosemide in chinchilla.

Previous investigation has suggested that the ototoxicity of furosemide is related to penetration of the drug into the inner ear and that active drug transport out of the inner ear may be responsible for maintaining the serum-perilymph drug concentration gradient. We further tested this hypothesis by investigating the endocochlear potential (ototoxicity) and furosemide perilymph concentrations after furosemide administration to chinchillas pretreated with the organic anion transport inhibitor, probenecid. Probenecid pretreatment attenuated the fall in endocochlear potential seen after furosemide (25 mg/kg i.v.): untreated, 58.6 +/- 27.0 mV; probenecid pretreatment, 14.1 +/- 11.9 mV (P less than .01). Furosemide concentrations in perilymph were correspondingly lower after probenecid (P less than .003), although serum furosemide concentrations were not affected by probenecid pretreatment. Diuresis, measured over an 8-hr period after furosemide, was also uneffected by probenecid. These results confirm the proposed relationship between inner ear furosemide concentrations and the occurrence of ototoxicity due to this drug. However, the determinants of penetration of this drug into the inner ear are unclear. The observation that probenecid pretreatment attenuates the ototoxic effect of furosemide while the diuretic effect is preserved suggests this drug combination warrants further investigation.

Animals↗
PubMed1982

A study of the probenecid effect on amino acid accumulation in kidney cortex slices.

The amount of amino acids accumulated by rat and mouse kidney cortex slices is determined by both membrane transport and intracellular metabolism, especially protein incorporation. Even with substrate concentrations of 100 microM up to 70% of the transported amino acids were found to be protein incorporated. Probenecid reduces the accumulation of the amino acids glycine, L-phenylalanine, L-valine, L-arginine, L-lysine, L-proline and alpha-AIB. At substrate concentrations of 100 microM the inhibition is between 28 and 66% (except alpha-AIB) with a probenecid concentration of 7.0 mM. Slight inhibitory effects were observed with 0.7 mM probenecid. The probenecid effect, however, is mainly on the protein incorporation. With 7.0 mM probenecid protein incorporation is reduced considerably, for some amino acids below 10% of the control values; small inhibitory effects were observed with concentrations of 0.7 mM. Amino acid transport is affected only slightly by probenecid. In consequence, higher accumulation rates of free amino acids may be measured after probenecid administration, preferentially with amino acids showing high initial incorporation rates.

Amino Acids↗
PubMed1995

Effects of probenecid and cimetidine on the renal excretion of 3'-azido-3'-deoxythymidine in rats.

The mechanisms underlying the inhibitory effects exerted by probenecid and cimetidine on the renal excretion of 3'-azido-3'-deoxythymidine (AZT) were investigated in rats in vivo. On i.v. administration, the findings indicated that both probenecid and cimetidine increased the plasma concentration of AZT and inhibited its renal excretion. To clarify the mechanisms underlying the interaction of these drugs with AZT and to elucidate the process of renal secretion of AZT, further investigation was performed, in which [3H]AZT (0.5 microM) was injected rapidly into the right renal artery, and its outflow profile from the right ureter was compared with that from the left ureter. In control experiments, 56.6% of the administered AZT was secreted from the right kidney, and it was calculated that the transcellular transit time of AZT in this process was 0.30 min. In the presence of 10 mM probenecid and of 10 mM cimetidine, the secretion of AZT was reduced to 15.3 and 32.3%, respectively, the inhibition induced by probenecid being more effective than that induced by cimetidine. However, the transcellular transit time of AZT increased to 0.53 and 1.21 min in the probenecid and cimetidine studies, respectively. Thus, cimetidine was more potent than probenecid in its effects on the transit time. These findings indicate that probenecid and cimetidine affect different steps in the renal secretion of AZT. It was therefore concluded that, on the renal plasma membrane, AZT is transported by anion transport systems, whereas on the brush border membrane, AZT is secreted by cation transport systems.

Animals↗
PubMed1976

Probenecid-induced effects on bile flow and biliary excretion of 3H-ouabain.

Probenecid-induced effects on bile flow and biliary excretion of exogenous compounds, e.g. 3H-ouabain were investigated on bile-fistula rats. Clearance measurements of 14C-mannitol under incresed doses of probenecid gave evidence that the drug acts at the canalicular site only. Biliary excretion of radioactivity after 14C-probenecid administration was found to be saturated at a dosage of 100 mg X kg-1. Probenecid exerts its choleretic effect by osmotic activity in a "bile acid-like" manner. This is confirmed by a close positive correlation between the excretion of radioactivity after treatment with 14C-probenecid and bile flow. The effects of probenecid on the biliary excretion of exogenous compounds, e.g. ouabain, imply beside choleresis also inhibitory effects on transport systems. As a result of both effects the biliary excretion of ouabain remains unchanged within a within a wide range of probenecid doses.

Animals↗
PubMed1998

A physiologically based kidney model for the renal clearance of ranitidine and the interaction with cimetidine and probenecid in the dog.

Ranitidine renal clearance was investigated in the beagle dog with or without concomitant infusion of cimetidine or probenecid. Ranitidine was excreted mainly by renal tubular secretion. Plasma clearance was reduced by probenecid from 198 +/- 47 to 119 +/- 41 mL min-1 (mean +/- SD.); renal clearance was reduced from 104 +/- 33 to 54 +/- 24 mL min-1 (p < 0.02) by probenecid and to 89 +/- 37 mL min-1 (NS) by cimetidine. Plasma and urine data were analysed simultaneously with a physiologically based kidney model and were both described adequately by the model, although tubular secretion could not be fully characterized as no saturation was achieved despite high dosages. Tubular secretion of ranitidine was simplified to first-order brush-border and basolateral transport across the proximal tubular cell. Basolateral transport was reduced (from 18.4 +/- 7.8 to 13.6 +/- 10.3 min-1 by cimetidine and 3.9 +/- 3.1 min-1 by probenecid), whereas no effect on brush-border exit was found. Estimated inhibition constants of cimetidine and probenecid were 62 and 4 micrograms mL-1, respectively. Summarizing, ranitidine renal pharmacokinetics were accurately described by the physiologically based kidney model presented in this paper. Model calculations suggest that interaction with cimetidine and probenecid results from competition for basolateral ranitidine uptake into tubular cells.

Animals↗
PubMed1978

The interaction between indomethacin and probenecid. A clinical and pharmacokinetic study.

The interaction between indomethacin and probenecid has been studied in 17 patients with rheumatoid arthritis with the use of a specific gas-liquid chromatographic method for the assay of indomethacin in plasma and urine. Probenecid in a dose of 0.5 gm twice daily improved the therapeutic response to indomethacin administered in a dose of 25 mg 3 times daily for a 3-wk period. There was an increase in the mean AUC of indomethacin in plasma from 2,553 +/- 213 hr ng/ml to 4,181 +/- 384 hr ng/ml when probenecid was given, but there was no change in the plasma half-life of indomethacin. There was a reduction in the mean plasma clearance of indomethacin from 174 +/- 21 ml/kg/hr to 107 +/- 14 ml/kg/hr when probenecid was added to the indomethacin therapy and a decrease in the apparent volume of distribution from 0,927 +/- 0.16 L/kg to 0.613 +/- 0.13 L/kg. There was no change in the amount of free indomethacin excreted in the urine during probenecid therapy but there was a reduction in the urinary excretion of free plus glucuronide conjugate of indomethacin from 8,967 +/- 867 microgram/day to 4,760 +/- 674 microgram/day, with a fall in the mean renal clearance of indomethacin glucuronide from 271 +/- 48 ml/min to 126 +/- 57.0 ml/min. The changes in the plasma indomethacin concentration profile during probenecid therapy are due to a decrease in the nonrenal clearance of indomethacin possibly because of reduced biliary clearance.

Adult↗
PubMed1982

Pharmacokinetics of probenecid following oral doses to human volunteers.

The pharmacokinetics of probenecid were examined following single 0.5-, 1.0-, and 2.0-g oral doses to healthy male volunteers. Doses were administered following overnight fast, according to a randomized design. Plasma levels of probenecid were determined by high-pressure liquid chromatography (HPLC), using sulfamethazine as the internal standard. Mean peak probenecid levels of 35.3, 69.6, and 148.6 micrograms/ml were obtained at 3-4 hr following the 0.5-, 1.0-, and 2.0-g doses, respectively. Probenecid levels from the 0.5- and 1.0-g doses declined in apparent monoexponential fashion, with mean elimination half-lives of 4.2 and 4.9 hr. Interpretation of the 2.0-g data by a kinetic model incorporating first-order elimination resulted in a plasma drug half-life of 8.5 hr. When first-order elimination was replaced by a Michaelis-Menten-type function, the mean value of the resulting Vm/Km ratios was 0.20, equivalent to a plasma drug half-life [0.693/(Vm/Km)] of 3.8 hr. Plasma probenecid curves from all three dosages were successfully fitted to the saturable elimination model using nonlinear regression and numerical integration routines. The results suggest that probenecid elimination may be saturable at therapeutic dose levels.

Administration, Oral↗
PubMed1998

Effect of oral probenecid coadministration on the chronic toxicity and pharmacokinetics of intravenous cidofovir in cynomolgus monkeys.

In animals and humans, intravenous administration of the antiviral nucleotide analogue cidofovir results in a dose-limiting nephrotoxicity characterized by damage to the proximal tubular epithelial cells. Probenecid, a competitive inhibitor of organic anion transport in the proximal tubular epithelial cells, was evaluated for its effect on the chronic toxicity and pharmacokinetics of cidofovir. Cynomolgus monkeys (5/sex/group) received cidofovir for 52 consecutive weeks as a once weekly intravenous bolus injection at 0 (saline), 0.1, 0.5, or 2.5 mg/kg/dose alone or at 2.5 mg/kg/dose in combination with probenecid (30 mg/kg/dose via oral gavage 1 h prior to cidofovir administration). Cidofovir-associated histopathological changes were seen only in the kidneys, testes, and epididymides. Nephrotoxicity (mild to moderate cortical tubular epithelial cell karyomegaly, tubular dilation, basement membrane thickening) was present only in monkeys receiving 2.5 mg/kg/dose cidofovir without probenecid. The incidence and severity of testicular (hypo- and aspermatogenesis) and epididymal (severe oligo- and aspermia) changes were increased in monkeys administered cidofovir at 2.5 mg/kg/dose, either alone or in combination with oral probenecid. Renal drug clearance was decreased between Weeks 1 and 52 in the 2.5 mg/kg/dose groups and resulted in an increased systemic exposure to cidofovir (as measured by AUC) that was significantly greater in monkeys administered cidofovir alone (312% increase in males, 98% in females) than in those coadministered probenecid (32% increase in males, 3% in females). These results demonstrate that oral probenecid coadministration protects against the morphological evidence of nephrotoxicity and the accompanying decrease in renal clearance in monkeys receiving chronic intravenous cidofovir treatment.

Administration, Oral↗
PubMed1977

The effect of L-tryptophan administration on the concentration of probenecid in plasma and cerebrospinal fluid in patients.

The administration of large doses of probenecid has been used to study the central nervous system metabolism of catecholamines and indoleamines in patients with affective disease. It has been reported that alterations of the binding of L-tryptophan to plasma albumin binding sites occur during probenecid administration. The present study sought to determine if the administration of large doses of L-tryptophan affected probenecid concentrations in cerebrospinal fluid and/or plasma. The data indicate that during L-tryptophan treatment, plasma probenecid concentrations are reduced but that no significant alterations in cerebrospinal fluid probenecid concentrations occur. This would suggest that the kinetics of the probenecid blockade of transport of acidic biogenic amine metabolites out of cerebrospinal fluid are not altered by L-tryptophan loading.

Adult↗
PubMed2001

Effect of probenecid on ventricular cerebrospinal fluid methotrexate pharmacokinetics after intralumbar administration in nonhuman primates.

PURPOSE: Intrathecal methotrexate (MTX) achieves high concentrations in the cerebrospinal fluid (CSF) following intralumbar administration. However, peak ventricular CSF MTX concentrations are highly variable and are < 10% of those achieved with intraventricular dosing. The objectives of this study were to evaluate the effect of intralumbar and intravenous probenecid on ventricular CSF MTX concentrations after intralumbar administration of MTX, and to compare the pharmacokinetics of MTX after intralumbar and intraventricular administration. METHODS: Nonhuman primates (Macaca mulatta) with permanently implanted catheters in the lateral and fourth ventricles received 0.5 mg intraventricular (lateral ventricle) MTX, or 0.5 mg intralumbar MTX with and without intralumbar or intravenous probenecid. Animals were kept prone for 1 h after MTX administration, and ventricular CSF was sampled up to 48 h from a fourth ventricular Ommaya reservoir. MTX concentrations were measured using the dihydrofolate reductase enzyme inhibition assay. Area under the ventricular CSF MTX concentration-time curve (AUC) was used as a measure of MTX exposure. RESULTS: Peak ventricular CSF MTX concentrations and AUCs were highly variable after intralumbar MTX administration. Ventricular CSF MTX AUCs increased by a mean of 3.2-fold after the addition of intralumbar probenecid. Intravenous administration of probenecid did not result in an increase in ventricular CSF MTX AUCs. Asymptomatic pleocytosis was observed in all animals after intralumbar probenecid administration. Ventricular CSF MTX concentrations and AUCs were less variable after intraventricular administration of MTX. CONCLUSION: The administration of intralumbar but not intravenous probenecid increases the ventricular CSF MTX exposure after intralumbar MTX administration.

Animals↗
PubMed1977

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 prolonged the half-life (T 1/2) of probenecid without changing its plasma-binding. As the rate of probenecid metabolism is decreased, its uricosuric action tends to be prolonged and the effect of PZA lessened. The PZA-suppressible urate level is increased to values well above control after the administration of probenecid; it is less after alkalinization of urine, although still larger than the value for PZA-suppressible urate after the administration of PZA alone. Urinary probenecid excretion is much greater when urine is alkalinized. These observed drug interactions, plus the known effect of probenecid to block secretion of PZA, have to be considered in evaluating the effect of the two drugs given together, compared to the effect of each drug given separately.

Adult↗
PubMed1985

Effect of probenecid on the disposition of captopril and captopril dimer in the rat.

The urinary excretion of captopril has been studied in a bladder-cannulated rat model and compared with that obtained after co-administration with probenecid. Probenecid reduced significantly the urinary excretion of captopril from 41% to 21% of the administered dose over a 3-hr period and significantly lowered urine flow rates. In addition, the effect of probenecid on plasma levels of captopril and total captopril (captopril plus disulfides) after oral administration of the disulfide prodrug captopril dimer (10 mg/kg) has been studied in a conscious rat preparation. Co-administration of probenecid (20 mg/kg) given either orally or intravenously increased both the plasma levels of captopril and total captopril (captopril plus captopril disulfides) over a 4-hr period. A prolonged significant inhibition of plasma ACE after co-administration of probenecid and captopril dimer suggests that probenecid may be useful to prolong the action of captopril or the prodrug captopril dimer.

Animals↗
PubMed1985

Effect of the organic acid transport inhibitor probenecid on renal cortical uptake and proximal tubular toxicity of hexachloro-1,3-butadiene and its conjugates.

Hexachloro-1,3-butadiene (HCBD), its glutathione conjugate (HCBD-GSH), cysteine conjugate (HCBD-CYS), and mercapturic acid derivative (HCBD-NAC) all produce acute necrosis of the pars recta of the proximal renal tubule in the rat. Previous studies have shown that radiolabel from administered HCBD appears to concentrate in the pars recta region. Renal uptake of radioactivity from HCBD-NAC was studied in rats by giving a single ip injection of the chemical and measuring its concentration in plasma and renal cortex 4 hr later. Cortex/plasma ratios (C/P) of HCBD-NAC were 4.35 +/- 0.21 (8 animals) at a dose of 64 mumol/kg and 10.4 +/- 0.55 (5) at a dose of 16 mumol/kg. These ratios were greater than that of inulin [C/P inulin = 1.5 +/- 0.2 (4)]. Thus cortical HCBD-NAC content was significantly greater than can be accounted for by glomerular filtration alone. Prior administration of probenecid (500 mumol/kg), a competitive inhibitor of organic acid transport, to animals receiving 16 or 64 mumol/kg of HCBD-NAC reduced the C/P to 1.03 +/- 0.09 (5) and 0.81 +/- 0.05 (8), respectively. Administration of probenecid in increasing doses (100, 200, 300, and 400 mumol/kg) to animals receiving 64 mumol/kg HCBD-NAC resulted in decreases of the C/P (2.59, 2.29, 1.35, and 0.84, respectively), suggesting a competitive inhibition of cortical HCBD-NAC uptake. The extent of covalently bound radioactivity from 64 mumol/kg HCBD-NAC was significantly greater in the renal cortex (1.11 +/- 0.2 nmol eq/mg protein) than in the liver (0.19 +/- 0.01 nmol eq/mg protein). Prior administration of probenecid (500 mumol/kg) reduced the renal cortical concentration of HCBD-NAC to 0.25 +/- 0.02 nmol eq/mg protein. Increasing doses of probenecid resulted in a progressive decrease in renal cortical covalent binding. When treatment with probenecid led to renal cortical concentrations of less than 120 nmol eq HCBD-NAC/g and an amount of covalently bound material less than 0.4 nmol eq/mg protein the animals were completely protected against the nephrotoxicity, as assessed by plasma urea and histopathological examination 24 hr after dosing. Prior administration of probenecid (500 mumol/kg) also protected rats against the nephrotoxicity produced by HCBD (192 mumol/kg), HCBD-GSH (47 mumol/kg), and HCBD-CYS (36 mumol/kg). It is suggested that the renal cortical accumulation and selective proximal tubular toxicity of HCBD and its conjugates is related to a carrier-mediated transport system.

Animals↗
PubMed1987

The effect of probenecid on acute N-(3,5-dichlorophenyl)succinimide-induced nephrotoxicity in the Fischer 344 rat.

N-(3,5-Dichlorophenyl)succinimide (NDPS), an experimental agricultural fungicide, has been shown to produce selective nephrotoxicity in rats. Previous studies have shown that a metabolite(s) of extrarenal origin contributes to acute NDPS-induced nephrotoxicity. The purpose of this study was to determine if the organic acid transport inhibitor probenecid could modify the renal toxicity produced by NDPS administration. Male Fischer 344 rats were administered a single intraperitoneal (i.p.) injection of probenecid (60, 90 and 120 mg/kg) or 0.9% saline (1.0 ml/kg) followed 30 min later by NDPS (0.4 or 1.0 mmol/kg, i.p.) or sesame oil (2.5 ml/kg, i.p.) Renal function was monitored at 24 h and 48 h. Probenecid (60 mg/kg) did not markedly alter NDPS-induced renal effects on either post-treatment day. However, pretreatment with probenecid (90 or 120 mg/kg) blocked or attenuated the diuresis, increased proteinuria, decreased tetraethylammonium (TEA), uptake, elevation in blood urea nitrogen (BUN) concentration and increased kidney weight produced by NDPS (0.4 mmol/kg) administration. Only increased kidney weight and BUN concentration, and decreased lactate-stimulated p-aminohippurate (PAH) uptake were altered by probenecid (120 mg/kg) pretreatment when NDPS (1.0 mmol/kg) was given. NDPS-induced changes in renal morphology were not prevented by pretreatment with any probenecid dose. These results suggest that at least one nephrotoxic metabolite of NDPS is an organic acid. However, this acidic metabolite might not be the major nephrotoxic metabolite or a precursor to the major nephrotoxic metabolite(s). The identity of these metabolites remains to be determined.

Animals↗