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PubMed1980

Effects of probenecid on transport and metabolism of cyclic AMP by isolated rabbit renal tubules.

The effects of probenecid on the transport and metabolism of cyclic [14C]-AMP were studied in isolated rabbit kidney cortex tubules. Incubation in a medium with 10-400 microM probenecid for 30 min caused a 30-70% decrease in the tubular uptake of labeled material from a medium containing 0.1 mM cyclic [14C]AMP. The radioactivity in the tubules, after 30 min incubation, with or without probenecid, was mostly in the form of inosine and hypoxanthine. The disappearance of external cyclic [14C]AMP was retarded by probenecid and the concentration ratio of cyclic AMP to inosine + hypoxanthine was increased. Cyclic AMP phosphodiesterase activities, from both the soluble and particulate fractions of the kidney, were inhibited by probenecid. These findings indicate that the changes caused by probenecid on the renal disposal of extracellular cyclic AMP can be accounted for by a decrease in the accumulation of the products of cyclic AMP metabolism secondary to inhibition of extracellular cyclic AMP phosphodiesterase activity.

Animals↗
PubMed2005

Influence of probenecid on the delivery of morphine-6-glucuronide to the brain.

The objective was to evaluate the influence of probenecid on the blood-brain barrier (BBB) transport of morphine-6-glucuronide (M6G). Microdialysis probes were placed in the striatum and into the jugular vein of Sprague-Dawley rats. Each probe was calibrated in vivo using retrodialysis by drug. M6G was administered as a 4-h exponential i.v. infusion, and the experiment was repeated the following day with the addition of probenecid. The data were analysed using NONMEM. An integrated model including the total arterial concentrations, the dialysate concentrations in brain and blood, and the recovery measurements, was developed. The extent of BBB transport, expressed as the ratio between clearance into the brain and clearance out of the brain (CL(in)/CL(out)), was estimated as 0.29 on both days, indicating that efflux transporters act on M6G at the BBB. However, the probenecid-sensitive transporters are not involved in the brain efflux, as the ratio was unaltered although probenecid was co-administered. In contrast, the systemic elimination of M6G decreased by 22% (p<0.05) upon probenecid co-administration. The half-life of M6G was longer in the brain than in blood on both experimental days (p<0.05). In conclusion, probenecid decreased the systemic elimination of M6G, but had no effect on the BBB transport of M6G.

Animals↗
PubMed1996

The effect of probenecid on the pharmacokinetics of zalcitabine in HIV-positive patients.

PURPOSE: The purpose of this study was to determine the potential effect of probenecid on the pharmacokinetics of zalcitabine in HIV-positive patients. METHODS: Twelve patients received single oral 1.5 mg doses of zalcitabine alone and during probenecid treatment (500 mg at 8 and 2 hours before and 4 hours after zalcitabine dosing) in an open-label, randomized two-way crossover study with a one-week washout period between treatments. Serial blood and urine samples were collected over a 24 hour period and assayed for zalcitabine by a modified GC/MS method. RESULTS: Coadministration of probenecid with zalcitabine resulted in a decrease in mean (%CV) renal clearance of zalcitabine from 310 (28%) ml/min when zalcitabine was given alone to 180 (22%) ml/min with probenecid and a prolonged half-life from 1.7 hours to 2.5 hours. Mean AUCs increased from 59 ng.h/ml when zalcitabine was given alone to 91 ng.h/ml when given with probenecid. Considering the short half-life of zalcitabine (1-3 hours) relative to its dosing schedule, the pharmacokinetic changes observed in this study are not expected to result in significant accumulation during chronic dosing. CONCLUSIONS: The results of this study show that co-administration of probenecid with zalcitabine results in a moderate decrease in renal clearance of zalcitabine due to inhibition of renal tubular secretion and a 50% increase in drug exposure. Although well tolerated in this single-dose study, patients taking this combination should be monitored closely for signs of toxicity and dosage reduction should be considered if warranted.

Administration, Oral↗
PubMed1995

Effect of probenecid on the enantioselective pharmacokinetics of oxprenolol and its glucuronides in the rabbit.

PURPOSE: To study the effect of probenecid on the stereoselective pharmacokinetics of oxprenolol and its glucuronides in the rabbit. METHODS: An oral dose of 50 mg/kg racemic oxprenolol was given to nine rabbits twice, in random sequence with and without the concurrent administration of probenecid. Oxprenolol enantiomers were determined in plasma and urine by an enantioselective HPLC method. Oxprenolol glucuronides were measured in plasma and urine after enzymatic hydrolysis. RESULTS: The disposition of the oxprenolol enantiomers in rabbits is stereoselective, mainly due to a difference in metabolism. Renal excretion is only a minor elimination route for unchanged oxprenolol, and the renal clearances of the enantiomers are similar. Pretreatment with probenecid did not affect the plasma concentrations of the oxprenolol enantiomers, but there was a slight decrease in their urinary excretion. The plasma concentrations of the oxprenolol glucuronides are much higher than those of the parent enantiomers, and those of (S)-glucuronide are about twice those of its antipode. About 10% of the oxprenolol dose is excreted in the urine as glucuronides. The renal clearances of both glucuronides are similar, and markedly higher than the creatinine clearance. After probenecid, the mean glucuronide plasma levels were markedly higher, with for both glucuronides a more than twofold increase in mean AUC. Probenecid decreased the renal clearance of both glucuronides to about 30%. Moreover, it decreased slightly the formation clearance of (S)-glucuronide, while the formation clearance of (R)-glucuronide was not significantly influenced. CONCLUSIONS: Our results show that in the rabbit, both oxprenolol glucuronide diastereomers are actively secreted by the kidney, and that this process is inhibited by probenecid.

Animals↗
PubMed1987

Effect of probenecid on cerebral and cisternal cerebrospinal fluid lactate content.

In this study, the cisternal CSF contents of lactate and glucose were sequentially measured in free-moving rats that had been administered probenecid, 200 mg/kg-1, drug diluent, or no injections. In animals receiving either no injections or injections of drug diluent, CSF lactate and glucose were constant over a 6-h period (93-106% of control), whereas rats receiving probenecid showed increased lactate at 1 and 2 h (170 and 125% control, respectively) and increased glucose at 1, 2, and 3 h (169, 141 and 129% control, respectively). Cerebral cortex content of energy metabolites and lactate and blood lactate levels were statistically unaltered at 0.5-6 h exposure to probenecid, whereas cerebral and blood glucose contents were increased after 1 and 2 h exposure to probenecid. Rats exposed to 5% O2 and probenecid for 0.5 h showed a statistically higher CSF lactate at 0.5 and 1.5 h reoxygenation (169 and 168% control, respectively). A similar effect was also seen in rats exposed to 5% O2 and the 5-hydroxyindoleacetic acid (5-HIAA) transport inhibitor Na divalproate. The results suggested that the increase in CSF glucose was secondary to a probenecid-induced elevation of blood glucose, whereas the increase in CSF lactate seemed to be secondary to a reduced rate of efflux of lactate from the CSF. It is suggested that it may be possible to increase the CSF lactate content by mechanisms that are independent of direct effects on the processes of cerebral energy metabolism.

Animals↗
PubMed1980

Prolongation of thiopentone anaesthesia by probenecid.

In a double-blind study, probenecid 0.5 or 1.0 g or placebo was given to 86 patients undergoing uterine curettage or gynaecological laparotomy 3 h before operation. The duration of anaesthesia in patients anaesthetized with thiopentone 7 mg kg-1 and premedicated with pethidine and atropine, was prolonged by 65% by probenecid 0.5 g, and by 46% by probenecid 1.0 g, compared with control (P < 0.05). In the absence of pethidine premedication, probenecid 0.5 g prolonged anaesthesia by 26% (P < 0.1). In patients without pethidine premedication anaesthetized with only thiopentone 4 mg kg-1 but who had no surgical stimulus during anaesthesia, probenecid increased the duration of the anaesthesia by 109% (P < 0.1). In this group the frequency of sleeping was 100%, as compared with 80% in the placebo-treated patients. Probenecid did not modify the response to pain and had no effect on apnoea, arterial pressure or heart rate.

Anesthesia, Intravenous↗
PubMed1983

Effect of probenecid on the pharmacokinetics of ceftizoxime.

The effect of probenecid on the pharmacokinetics of ceftizoxime was studied. Twelve healthy male volunteers first received 1 g of ceftizoxime either by iv rapid injection or by im injection. One week later, each subject was again given a similar dose of ceftizoxime, one hour after the ingestion of 1 g of probenecid. Serum and urinary concentrations were determined by a HPLC method. Ceftizoxime half-life was increased by probenecid from 1.7 to 2.3 h in the iv group, and 1.9 to 2.8 h in the im group (P less than 0.05, paired t-test). Probenecid increased the area under the serum concentration-time curve by 49% in both groups. There was no significant change in the volume of distribution following probenecid. This study confirms that ceftizoxime is eliminated by glomerular filtration and tubular secretion and that the latter is inhibited by probenecid.

Adult↗
PubMed2001

Effects of probenecid on renal function in surgical patients anesthetized with low-flow sevoflurane.

BACKGROUND: Dehydrofluorination of sevoflurane by carbon dioxide absorbents in anesthesia machines produces compound A, which is nephrotoxic in rats. Several clinical studies indicate that prolonged low-flow sevoflurane anesthesia is associated with an increased urinary excretion of biochemical markers, such as protein. Probenecid, a competitive inhibitor of organic anion transport, diminishes compound A nephrotoxicity in rats. The purpose of the present study was to examine the effects of low- and high-flow sevoflurane anesthesia on urinary excretion of biochemical markers in humans and to examine the effects of probenecid on urinary excretion of these markers. METHODS: Elective surgical patients (n = 64) were assigned to four groups (n = 16 each): low-flow sevoflurane plus probenecid (LSP), low-flow sevoflurane (LS), high-flow sevoflurane plus probenecid (HSP), and high-flow sevoflurane (HS). Probenecid (2.0 g) was administered orally 2 h before the induction of anesthesia in both the LSP and HSP groups. Nothing was administered orally 2 h before the induction of anesthesia in either the LS or HS groups. All patients underwent prolonged low-flow (1 l/min) or high-flow (6 l/min) sevoflurane anesthesia. Urinary excretion of protein, albumin, beta(2)-microglobulin, glucose, and N-acetyl-beta-d-glucosaminidase was measured for up to 7 days postoperatively. RESULTS: Sevoflurane doses were similar in all four groups. There were no differences in blood urea nitrogen, creatinine, or creatinine clearance among the four groups after anesthesia. Average values for urinary excretion of protein, beta(2)-microglobulin, and N-acetyl-beta-d-glucosaminidase in the LS group were significantly higher than those in the other groups (LSP, HSP, HS; P < 0.05). There was no significant difference between the LS and LSP groups in average values for urinary excretion of albumin and glucose, although there were significant differences between the LS and both high-flow sevoflurane groups (HSP, HS). CONCLUSIONS: Low-flow sevoflurane, which produces a sevenfold higher compound A exposure than high-flow sevoflurane, resulted in significant increases of several biochemical markers in half of the patients. Probenecid appears to provide protection against these renal effects.

Adult↗
PubMed1987

Probenecid interferes with the natriuretic action of furosemide.

The interaction between probenecid and furosemide was studied in eight hospital patients (ages 20-65 years) who had been treated with oral furosemide, 40 mg daily, and moderate salt restriction for 10 days or longer. After stabilization of drug therapy and diet for at least 3 days, probenecid, 0.5 g twice a day, was given for 3 days and then discontinued. The 24-h urinary sodium excretion (UNaV) significantly decreased from 56.3 +/- 7.2 to 35.9 +/- 7.1 mmol/day when probenecid was added to the treatment regimen (p less than 0.01), and then significantly increased to 61.7 +/- 10.3 mmol/day after probenecid was discontinued (p less than 0.01). Parallel with the changes in UNaV, there were also significant corresponding changes (p less than 0.01) in urinary excretion of uric acid (392.4 +/- 46.5, 600.9 +/- 102.1, and 345.0 +/- 33.2 mg/day, respectively), renal clearance of uric acid (3.7 +/- 0.3, 14.3 +/- 2.4, and 4.1 +/- 0.3 ml/h/kg, respectively), and serum uric acid concentration (7.7 +/- 0.5, 3.3 +/- 0.2, and 6.3 +/- 0.3 mg/dl, respectively). Before and after discontinuing probenecid therapy, there were no significant differences in these parameters (p greater than 0.05). In conclusion, the natriuretic action of furosemide was attenuated by concurrent probenecid therapy, probably owing to a reduction of furosemide delivery to the luminal side of renal tubules.

Adult↗
PubMed2004

Open randomized study of pyrimethamine-sulphadoxine vs. pyrimethamine-sulphadoxine plus probenecid for the treatment of uncomplicated Plasmodium falciparum malaria in children.

BACKGROUND: Increasing drug resistance in Plasmodium falciparum has necessitated renewed search for cheap, effective alternatives to commonly available antimalarials, chloroquine and pyrimethamine-sulphadoxine, for the treatment of malaria in Africa. Probenecid, an inhibitor of organic anion transporters and multiresistance-associated proteins, can chemosensitize P. falciparum to pyrimethamine and sulphadoxine in vitro, but the clinical significance is unclear. We assessed the safety, treatment efficacy, and effects on gametocyte carriage of adding probenecid to pyrimethamine-sulphadoxine. METHODS: We evaluated 151 children aged 12 years or younger who had uncomplicated P. falciparum malaria. Patients were randomly assigned pyrimethamine-sulphadoxine (25 mg/kg of the sulphadoxine component) or pyrimethamine-sulphadoxine as above plus probenecid 20-25 mg/kg of bodyweight in two divided doses daily for 3 days. The primary endpoints were parasitological cure rates on days 14 and 28. RESULTS: Both regimens were well tolerated; no child was withdrawn because of drug intolerance. Fever (1.9 +/- 1.1 vs. 2.4 +/- 1.2 days, P = 0.02) and parasite clearance (2.3 +/- 0.9 vs. 2.7 +/- 1.1 days, P = 0.04) were significantly shorter, and the parasitological cure rate on day 14 (96.2%vs. 83.5%, P = 0.02) but not day 28 (79.4%vs. 72.6%, P = 0.4), was significantly higher in children treated with pyrimethamine-sulphadoxine-probenecid than in those treated with pyrimethamine-sulphadoxine. Gametocyte carriage was similar with both treatment regimens. CONCLUSIONS: The combination of pyrimethamine-sulphadoxine, and probenecid, at a relatively moderate dose, improved treatment efficacy but had no effect on gametocyte carriage. The pyrimethamine-sulphadoxine-probenecid combination merits further evaluation as a potential treatment for use in Nigeria.

Acute Disease↗
PubMed1987

Probenecid-induced accumulation of 5-hydroxyindoleacetic acid and homovanillic acid in rat brain.

The accumulation of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in rat brain has been examined after probenecid infusion over 8 h. At plasma probenecid concentrations of 200-400 micrograms mL-1 a steady state level in the accumulation of 5-HIAA and HVA was achieved, the increase above the endogenous levels being 135% and 65%, respectively. When the plasma concentration of probenecid rose above 400 micrograms mL-1 there was further accumulation of both 5-HIAA and HVA probably induced by increased neuronal activity or toxicity due to probenecid. The explanation for the plateau of 5-HIAA and HVA obtained over the plasma probenecid concentration interval of 200-400 micrograms mL-1 could be that the levels were reached when there was complete inhibition of active transport, and when the rate of formation of the metabolites equalled the rate of elimination by alternative routes i.e. bulk flow and diffusion. Therefore when probenecid is used to inhibit the active transport of acid monoamine metabolites across the blood-brain barrier, its plasma concentration should be within the range of 200-400 micrograms mL-1.

Animals↗
PubMed2006

Inhibition of oat3-mediated renal uptake as a mechanism for drug-drug interaction between fexofenadine and probenecid.

Fexofenadine, a nonsedating antihistamine drug, is effective for the treatment of seasonal allergic rhinitis and chronic urticaria. Simultaneous administration of probenecid increases the plasma concentration of fexofenadine due to an inhibition of its renal elimination in healthy volunteers (Clin Pharmacol Ther 77:17-23, 2005). The purpose of the present study is to investigate the possibility that the drug-drug interaction between fexofenadine and probenecid involves the renal basolateral uptake process. The uptake of fexofenadine was determined in HEK293 cells expressing human organic anion transporter 1 (OAT1/SLC22A6), OAT2 (SLC22A7), OAT3 (SLC22A8), and organic cation transporter 2 (OCT2/SLC22A2). Only hOAT3-HEK showed a significantly greater accumulation of fexofenadine than that in vector-HEK, which was saturable with K(m) and V(max) values of 70.2 microM and 120 pmol/min/mg protein, respectively. Inhibition potency of probenecid for the uptake of fexofenadine was compared between hOAT3 and organic anion-transporting peptide 1B3 (hOATP1B3), a transporter responsible for the hepatic uptake of fexofenadine (Drug Metab Dispos 33:1477-1481, 2005). The K(i) values were determined to be 1.30 and 130 microM for hOAT3 and hOATP1B3, respectively, with Hill coefficients of 0.76 and 0.64, respectively. The K(i) value of probenecid for hOAT3, but not for hOATP1B3, was significantly lower than the maximum unbound plasma concentration of probenecid at clinical dosages. These results suggest that the renal drug-drug interaction between fexofenadine and probenecid is probably explained by an inhibition of the renal uptake of fexofenadine via hOAT3, at least in part.

Anti-Allergic Agents↗
PubMed1981

Failure of probenecid to alter the pharmacokinetics of ceforanide.

This investigation evaluated the effect of probenecid on ceforanide concentrations in eight healthy volunteers. Each volunteer was given 1 or 2 g of ceforanide either alone or with 1 g of probenecid. Concentrations of ceforanide in plasma, urine, and saliva were then measured. Probenecid did not alter the plasma concentrations of ceforanide, nor did it affect the urinary excretion of this agent. Ceforanide was not secreted into saliva in any detectable amount either when administered alone or with probenecid. It is not clear why probenecid has a negligible effect on ceforanide concentrations in plasma. It may be that tubular secretion plays less of a role in the excretion of ceforanide than expected, or that the physical properties of ceforanide prevent probenecid from affecting its excretion.

Adult↗
PubMed1999

Effect of probenecid on the renal excretion mechanism of a new carbapenem, DA-1131, in rats and rabbits.

The effects of probenecid, an anion transport inhibitor, on the renal excretion mechanism of a new anionic carbapenem, DA-1131, were investigated after a 1-min intravenous infusion of DA-1131 at 100 mg/kg of body weight to rabbits and 50 mg/kg to rats with or without probenecid at 50 mg/kg for both species. In control rabbits, the renal clearance (CLR) of DA-1131 and the glomerular filtration rate based on creatinine clearance (CLCR) were 6.14 +/- 2.09 and 2.26 +/- 0.589 ml/min/kg, respectively. When considering the less than 10% plasma protein binding of DA-1131 in rabbits, renal tubular secretion of DA-1131 was observed in rabbits. The CLR of DA-1131 (3. 87 +/- 0.543 ml/min/kg) decreased significantly with treatment with probenecid in rabbits, indicating that the renal tubular secretion of DA-1131 was inhibited by probenecid. However, in control rats, the CLR of DA-1131 (5.80 +/- 1.94 ml/min/kg) was comparable to the CLCR (4.29 +/- 1.64 ml/min/kg), indicating that DA-1131 was mainly excreted by glomerular filtration in rats. Therefore, it could be expected that the CLR of DA-1131 could not be affected by treatment with probenecid in rats; this was proved by a similar CLR of DA-1131 with treatment with (6.93 +/- 0.675 ml/min/kg) or without (5.80 +/- 1.94 ml/min/kg) probenecid. Therefore, the renal secretion of DA-1131 is a factor in rabbits but is not a factor in rats.

Animals↗
PubMed2002

Multiple interactions of cimetidine and probenecid with valaciclovir and its metabolite acyclovir.

The effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite acyclovir have been investigated. Twelve healthy male volunteers participated in this open single-dose study with a four-way-crossover randomized and balanced design. At the first of four administrations, volunteers in four groups received 1 g of valaciclovir alone, valaciclovir with 1 g of probenecid, valaciclovir with 800 mg of cimetidine, or valaciclovir with a combination of probenecid and cimetidine. At three subsequent administrations, drug regimens were alternated among groups so that each group received each regimen. Probenecid and cimetidine increased the mean maximum concentrations in serum (C(max)) of valaciclovir by 23 and 53% and the areas under the concentration-time curves (AUC) for valaciclovir by 22 and 73%, respectively; probenecid and cimetidine also increased the mean acyclovir C(max) by 22 and 8% and its AUC by 48 and 27%, respectively. The combination had a greater effect than either drug alone. Their effects may be due to competitive inhibition of membrane transport of valaciclovir and acyclovir in the liver and kidney. Neither cimetidine nor probenecid affected the absorption of valaciclovir. Both probe drugs reduced the rate of valaciclovir metabolism but not its extent. These pharmacokinetic modifications did not affect the tolerability of valaciclovir.

Acyclovir↗
PubMed1974

Effect of probenecid on cerebrospinal fluid concentrations of penicillin and cephalosporin derivatives.

Probenecid may elevate the cerebrospinal fluid (CSF) concentration of penicillin G by inhibiting the excretion of organic acids from CSF. We have studied this phenomenon with various penicillin and cephalosporin derivatives. Penicillin concentrations were determined in rabbits under steady-state conditions before and after intravenous probenecid administration. With both low-dose and high-dose probenecid, CSF penicillin levels increased two to three times as did CSF concentration as a percentage of serum level. The same probenecid effect was consistently demonstrated in animals with experimental pneumococcal meningitis. Probenecid likewise increased the CSF concentration of ampicillin, carbenicillin, nafcillin, cephacatrile, and cefazolin. Probenecid may prove useful in certain bacterial infections where high CSF antibiotic levels are necessary.

Animals↗
PubMed1992

Comparison of fleroxacin and penicillin G plus probenecid in the treatment of acute uncomplicated gonococcal infections.

OBJECTIVE: To investigate the activity of fleroxacin in acute uncomplicated infections with N. gonorrhoeae in comparison with conventional penicillin G plus probenecid treatment. DESIGN: Multicentre open label randomised parallel group study. SUBJECTS: Male patients aged 18 years or over from university departments of urology, epidemiology and dermatology and a clinic for sexually transmitted diseases. INTERVENTIONS: Two hundred and sixty male patients were randomly assigned to treatment with either a single oral dose of fleroxacin 400 mg (130 patients) or a single intramuscular dose of penicillin G (2.4 or 5.0 mega units) plus a single oral dose of probenecid 1 gram (130 patients). Efficacy and safety assessments were undertaken at follow-up (3-14 days after treatment). Efficacy was assessed as bacteriological outcome of treatment. Safety was assessed by evaluation of adverse events, laboratory abnormalities and changes in vital signs. RESULTS: Two hundred and twenty four patients (114 in the fleroxacin group and 110 in the penicillin plus probenecid group) were evaluated for efficacy. Bacteriological cures were achieved in 100% of patients in the fleroxacin group and 97% of patients in the penicillin plus probenecid group. There was no statistically significant difference between the two groups in this respect (Fisher exact test, p = 0.25). Clinical cures were achieved in 100% of patients receiving fleroxacin and 95% of patients receiving penicillin plus probenecid. Safety analyses were undertaken on 255 patients (126 in the fleroxacin group and 129 in the penicillin plus probenecid group). No adverse events were reported for either treatment group, and no clinically relevant laboratory abnormalities were apparent. Thus, there appeared to be no difference in the efficacy or safety of these two treatments when used to treat acute, uncomplicated urethral gonorrhoea in males. CONCLUSIONS: In this study fleroxacin proved to be highly effective therapy for uncomplicated gonococcal urethritis in males and may provide a favourable alternative to standard treatment.

Acute Disease↗