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PubMed2005

MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid.

ATP binding cassette (ABC) multidrug transporters such as P-glycoprotein (P-gp, ABCB1) and BCRP (ABCG2) confer resistance against anticancer drugs and can limit their oral availability, thus contributing to failure of chemotherapy. Like P-gp and BCRP, another ABC transporter, MRP2 (ABCC2), is found in apical membranes of pharmacologically important epithelial barriers and in a variety of tumors. MRP2 transports several anticancer drugs and might thus have a similar impact on chemotherapy as P-gp and BCRP. We here show that human MRP2 transduced into epithelial MDCKII cells efficiently transported the taxane anticancer drugs paclitaxel and docetaxel and that this transport could be substantially stimulated with the drug probenecid, a representative of a range of MRP2-stimulating drugs. Transport of 2 previously identified MRP2 substrates, etoposide and vinblastine, was likewise stimulated by probenecid. MRP2 further conferred substantial resistance against paclitaxel toxicity, and this resistance was 2.7-fold stimulated by probenecid. Our data indicate that MRP2 function might affect chemotherapy with taxanes, potentially influencing both tumor resistance and taxane pharmacokinetics. Moreover, coadministration of probenecid and other MRP2-stimulating drugs might lead to unforeseen drug-drug interactions by stimulating MRP2 function, potentially leading to suboptimal levels of taxanes and other anticancer drugs in plasma and tumor.

Animals↗

PubMed1976

Urinary excretion of probenecid and its metabolites in humans as a function of dose.

A GLC assay was used to study the excretion of probenecid and its metabolites in the urine of human subjects following oral doses of 0.5, 1, and 2 g. From 75 to 88% of the dose was found in the urine. The major metabolite, probenecid acyl glucuronide, accounted for 34-47% of the dose. Approximately equal amounts (10-15%) of the mono-N-propyl, secondary alcohol, and carboxylic acid metabolites were excreted in the unconjugated from with only traces in the conjugated form. The primary alcohol metabolite was not found in measurable amounts. The terminal half-lives for excretion of all metabolites were in the range of 4-6 hr, were independent of dose, and were limited by their rates of formation. A prolonged time course of excretion of the metabolites, particularly at higher doses, suggests that probenecid, being poorly soluble in water, precipitates from solution in the GI tract, forming a depot of drug from which absorption is dissolution rate limited. The urinary excretion of unchanged probenecid, which accounts for 4-13% of the dose, is dependent on both the pH and flow rate of urine.

Adult↗

PubMed1987

Non-linear elimination and protein binding of probenecid.

Six healthy volunteers were given probenecid 0.5, 1 and 2 g p.o. and 0.5 g i.v. The protein binding of probenecid at different concentrations in human plasma was estimated by equilibrium dialysis. The free fraction was found to increase nonlinearly with increasing total probenecid concentration, up to a maximum free fraction of 26%. The plasma concentration-time data after the oral doses were described by a one-compartment open model with first-order absorption and Michaelis-Menten elimination. The mean absorption rate constant 0.0072 min-1 was dose-independent, and the maximal rate of elimination (mean 1429 micrograms/min) did not differ between doses whether calculated from the total or free concentrations. The Michaelis-Menten constant constant decreased significantly from 67.1 to 55.5 micrograms/ml as the dose increased from 1 g to 2 g, while the unbound Michaelis-Menten constant remained unchanged. The elimination of probenecid after the 0.5 g dose was in the linear region of the Michaelis-Menten elimination when calculated from the total and the free concentrations. The volume of distribution increased only slightly from 9.5 to 11.41 as the dose increased from 0.5 to 2 g, but the unbound volume of distribution decreased significantly from 164 to 99 1. Absorption was complete and was independent of the dose administered.

Absorption↗

PubMed1980

Quantitation of CSF concentrations and biological activity of probenecid metabolites.

The concentrations of probenecid and four of its metabolites have been examined in plasma and CSF by electron capture gas chromatography after extractive methylation. The plasma concentration of each of the metabolites was in the range 1,5-15 micrograms/ml and constituted less than 10% of the parent compound. The penetration into CSF of the metabolites was lower than that of probenecid. The concentration of each of the metabolites was below 0,2 microgram/ml and the total concentration never exceeded 10% of the probenecid concentration. The inhibitory effect of the metabolites on uptake was tested in rabbit renal cortex using 3H-p-amino-hippuric acid. The inhibitory effect was low. From the low activity and relatively low concentrations of the metabolites do not contribute to the probenecid-induced blocking effect of acid transport from the CSF.

Animals↗

PubMed1994

Probenecid inhibits the glucuronidation of indomethacin and O-desmethylindomethacin in humans. A pilot experiment.

Indomethacin is metabolized in humans by O-demethylation, and by acyl glucuronidation to the 1-O-glucuronide. Indomethacin, its metabolite, and their conjugates can be measured directly by gradient high-pressure liquid chromatographic analysis without enzymic deglucuronidation. The pharmacokinetic profile of indomethacin and some preliminary pharmacokinetic parameters of indomethacin obtained from one human volunteer are given. In plasma only the parent drug indomethacin is present, while in urine the acyl and ether glucuronides are present in high concentrations. This confirms other reports that indomethacin and O-desmethylindomethacin may be glucuronidated in the kidney. Probenecid is a known substrate for renal glucuronidation. If indomethacin is glucuronidated in the human kidney like probenecid, then this glucuronidation might be reduced or inhibited under probenecid co-medication. This pilot experiment shows that probenecid reduced the acyl glucuronidation of indomethacin by 50% and completely inhibited the formation of O-desmethylindomethacin acyl and ether glucuronide.

Chromatography, High Pressure Liquid↗

PubMedDate not supplied

Simultaneous kinetic modelling of plasma levels and urinary excretion of salicyluric acid, and the influence of probenecid.

In a fundamental study on the effect of probenecid on the plasma kinetics and the renal handling of some organic anions known to be transported by the tubular secretion mechanism in the mammalian kidney, we measured plasma levels and urinary excretion rates of salicyluric acid in male Beagle dogs, after intravenous application of salicyluric acid, with and without co-administration of probenecid. The animals were anaesthetized with sodium pentobarbital (30 mg/kg) and provisions were made for blood and urine sampling. In order to obtain a sufficiently high and constant urine flow, an infusion of a solution containing 5% inulin (2 ml/min) was given throughout an experiment. Inulin was added for measurement of the glomerular filtration rate. Linear plots of the urinary excretion rate against the average plasma concentration of each urine collection period were drawn as an illustrative way to depict the relation between plasma concentration and urinary excretion rate. In order to quantify the effect of probenecid on the plasma kinetics and the renal handling of salicyluric acid, we conceived a dynamic model, able to describe changes in plasma kinetics as well as in urinary excretion. The effect of probenecid on the pharmacokinetics of salicyluric acid can be adequately described in terms of a non-competitive inhibition of the tubular secretory mechanism for salicyluric acid. Parameters for the description of this interaction were estimated by a simulation procedure with the aid of the computer program CSMP III.

Animals↗

PubMed1976

Effect of probenecid on endogenous and exogenous 3,4-dihydroxyphenylacetic acid and homovanillic acid in the rat brain.

The two dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured in corpus striatum and hippocampus in rats after an intracerebroventricular injection of DOPAC or HVA. Probenecid 200 mg/kg i.p. increased the concentration of HVA by the same factor in both control animals and animals treated with HVA. Probenecid had no effect on the DOPAC concentration in control animals or in animals treated with DOPAC. After DOPAC intraventricularly some increase in the HVA concentration could be seen. Pargyline 75 mg/kg was given i.m. and the decline of HVA and DOPAC in corpus striatum was compared in animals with or without probenecid treatment (200 mg/kg i.p.). In the control animals DOPAC declined more rapidly than did HVA. In the probenecid-treated animals there was no change in the DOPAC curve while the HVA showed a slower elimination but still with an exponential curve. The conclusion is drawn that there is an active mechanism for the excretion of DOPAC which is not identical with the excretion mechanism for HVA. A considerable part of the dopamine is directly deaminated to DOPAC in vivo and some of this DOPAC is probably O-methylated to HVA.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1982

Potentiation of barbiturate- and halothane-induced hypnosis after probenecid or sulfinpyrazone pretreatment.

The uricosuric agent, probenecid, when administered prior to systemic administration of pentobarbital led to a decreased latency, to loss of righting reflex and to a potentiation of the duration of hypnosis. This potentiation was dose-related and doses of probenecid below 50 mg/kg (i.p.) were without effect. Pretreatment of rats with sulfinpyrazone, another uricosuric agent, yielded similar results. Pretreatment of animals with probenecid shortened the latency to onset of hypnosis induced by halothane (i.p.) and increased the duration of loss of righting reflex, 3-fold. Both sulfinpyrazone and probenecid, administered prior to 1.0% inhalation halothane exposure, shortened the latency to onset of hypnosis in doses as small as 10 mg/kg, much less than the doses required to affect significantly pentobarbital-induced hypnosis. The results, as yet, do not indicate a plausible mechanism of action, but do expose a potentially useful drug interaction which may be of clinical use.

Animals↗

PubMed1990

Increase in the acute toxicity and brain concentrations of chlorophenoxyacetic acids by probenecid in rats.

1. Probenecid increased the acute toxicity of chlorophenoxyacetic acids (2,4-D, 2,4,5-T and MCPA) in rats. 2. Probenecid increased the brain to plasma ratios of all the three 14C-labelled chlorophenoxyacetic acids. The increase was due only partly to the displacement of chlorophenoxyacids from their binding sites in rat plasma proteins by probenecid. 3. Probenecid did not change significantly the intracerebral distribution pattern of 14C-labelled chlorophenoxyacetic acids.

2,4,5-Trichlorophenoxyacetic Acid↗

PubMed2005

Different effects of three transporting inhibitors, verapamil, cimetidine, and probenecid, on fexofenadine pharmacokinetics.

OBJECTIVE: Fexofenadine is a substrate of P-glycoprotein and organic anion transporting polypeptides. The aim of this study was to compare the inhibitory effects of different transporting inhibitors on fexofenadine pharmacokinetics. METHODS: Twelve male volunteers took a single oral 120-mg dose of fexofenadine. Thereafter three 6-day courses of either 240 mg verapamil, an inhibitor of P-glycoprotein, 800 mg cimetidine, an inhibitor of organic cation transporters, or 2000 mg probenecid, an inhibitor of organic anion transporting polypeptides, were administered on a daily basis in a randomized fashion with the same dose of fexofenadine on day 6. Plasma and urine concentrations of fexofenadine were monitored up to 48 hours after dosing. RESULTS: Verapamil treatment significantly increased the peak plasma concentration by 2.9-fold (95% confidence interval [CI], 2.4- to 4.0-fold) and the area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of fexofenadine by 2.5-fold (95% CI, 2.0- to 3.3-fold). No changes in any plasma pharmacokinetic parameters of fexofenadine were found during cimetidine treatment. AUC(0-infinity) was slightly but significantly increased during probenecid treatment by 1.5-fold (95% CI, 1.1- to 2.4-fold). Renal clearance of fexofenadine was significantly decreased during cimetidine treatment to 61% (95% CI, 50%-98%) and during probenecid treatment to 27% (95% CI, 20%-58%) but not during verapamil treatment. CONCLUSION: This study suggests that verapamil increases fexofenadine exposure probably because of an increase in bioavailability through P-glycoprotein inhibition and that probenecid slightly increases the area under the plasma concentration-time curve of fexofenadine as a result of a pronounced reduction in renal clearance. However, it may be difficult to explain these interactions by simple inhibitory mechanisms on target transporters.

Adult↗

PubMed1979

Selected ion monitoring assay for biogenic amine metabolites and probenecid in human lumbar cerebrospinal fluid.

Details are presented of an improved selected ion monitoring assay for the major biogenic amine metabolites and probenecid in human lumbar cerebrospinal fluid (CSF). The metabolites and probenecid are simultaneously extracted with ethyl acetate from an acidified aqueous phase, and are simultaneously converted to pentafluoropropionyl esters by reaction with pentafluoropropionic anhydride and pentafluoropropanol. The esters of the metabolites are analyzed following a single injection of the derivatized sample onto the gas chromatographic column, while the ester of probenecid is analyzed following a separate injection onto the gas chromatographic column. Quantitation is achieved using for internal standards dueterated analogues of the metabolites and a chemical analogue of probenecid. Data are presented on the concentration of free and conjugated forms of the metabolites in lumbar CSF taken from healthy volunteers.

Biogenic Amines↗

PubMedDate not supplied

Ceftriaxone versus cefazolin with probenecid for severe skin and soft tissue infections.

To evaluate the hypothesis that a single daily administration of cefazolin and probenecid and a single daily administration of ceftriaxone and probenecid would be equally effective, in combination with oral antibiotics, for the outpatient treatment of skin and soft tissue infections, a randomized, double-blind study was completed. Patients presenting to the Emergency Department with the primary diagnosis of cellulitis or soft tissue infection, excluding patients requiring immediate hospital admission, received either 2 g of ceftriaxone or 2 g of cefazolin, each with 1 g of probenecid, on a daily basis as outpatients from the Emergency Department. The patients were given a prescription for oral penicillin and cloxacillin for independent procurement. Outcome was assessed based on reduction in the size of the infected area, and the need for additional treatment (other antibiotics or hospital admission). A total of 194 patients were randomized to receive ceftriaxone (96) or cefazolin (98). There was no statistical difference in cause of infection, site of infection, duration of treatment, noncompliance or need for incision or drainage of the wound. The outcome, as determined by the ratio of the involved infected area on initial and last treatment day, and the frequency of failure were similar. The single daily administration of 2 g of either cefazolin, in combination with probenecid, or ceftriaxone are equivalent in efficacy in the outpatient treatment of skin and soft tissue infections. There is the potential for significant cost savings in utilizing outpatient cefazolin therapy over ceftriaxone for treatment of these infections.

Ambulatory Care↗

PubMed2001

Effect of probenecid on fluorescein transport in the central nervous system using in vitro and in vivo models.

PURPOSE: The purpose of this study was to characterize the function of multidrug resistance-associated proteins (MRPs) (or MRP-like organic anion transport systems) in the blood-brain harrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) using both an in vitro BBB model and an in vivo microdialysis model. METHODS: In vitro functional studies were performed using bovine brain microvessel endothelial cells (BBMEC). The accumulation of fluorescein, an anionic fluorescent dye, in BBMEC was determined with and without the presence of inhibitors of various efflux transport proteins. In vivo microdialysis simultaneously monitored fluorescein concentrations in cortical extracellular fluid and cerebrospinal fluid. The effect of probenecid on the in vivo distribution of fluorescein was studied using a balanced crossover design in the rat. RESULTS: In vitro experiments showed that probenecid, indomethacin, LY-329146, and all MRP inhibitors significantly increased (two- to threefold) the accumulation of fluorescein in BBMEC, whereas LY-335979, a P-gp inhibitor, had no effect on the accumulation of fluorescein. Probenecid significantly increased fluorescein plasma concentration and the plasma free fraction in vivo. The distribution of fluorescein across the BBB and BCSFB was enhanced by 2.2- and 1.9-fold, respectively, when probenecid was coadministered, even after correction for increased fluorescein plasma concentrations and free fraction. CONCLUSIONS: These results demonstrate that MRPs or MRP-like transport system(s) may play an important role in fluorescein distribution across both BBB and BCSFB. This study showed that microdialysis proved to be a powerful in vivo technique for the study of transport systems in the central nervous system, and in vitro/in vivo correlations are possible using these model systems.

Algorithms↗

PubMed1980

Effect of probenecid on the kinetics of epsilon-aminocaproic acid.

Healthy male subjects received, 1 wk apart, single oral doses of epsilon-aminocaproic acid (EACA) 100 mg/kg alone, EACA within probenecid (0.5 gm), or EACA 2 hr after 2.0 gm probenecid. Probenecid (2.0 gm) reduced the 8-hr urinary clearance and recovery of EACA by 50% without affecting plasma kinetics. Recovery of EACA in urine rose to 78% of the dose 48 hr after EACA. Plasma clearance of EACA did not differ from control EACA urinary clearance when 0.5 gm probenecid was given with EACA. In both cases all the EACA dose was recovered in urine within 8 hr.

Aminocaproates↗

PubMed1989

Alteration of zidovudine pharmacokinetics by probenecid in patients with AIDS or AIDS-related complex.

The anti-human immunodeficiency virus drug zidovudine is metabolized extensively in human beings to the 5'-glucuronide (GAZT) and is cleared rapidly, resulting in a short half-life and the need for frequent dosing. This study explores whether probenecid, which is also metabolized by glucuronidation, reduces zidovudine clearance when zidovudine is administered orally to patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). The mean zidovudine plasma levels were significantly higher after concurrent administration of probenecid than in its absence, resulting in a twofold increase in the mean AUC, a corresponding decline in the apparent total clearance, and a prolongation in the mean half-life. Similar alterations were observed in GAZT disposition. There was a marked reduction in the urinary excretion ratio of GAZT to zidovudine and a decline in the renal clearance of GAZT after probenecid coadministration. Probenecid inhibits zidovudine glucuronidation and renal excretion of GAZT.

AIDS-Related Complex↗

PubMed1989

Probenecid-induced changes in the clearance of carprofen enantiomers: a preliminary study.

Probenecid inhibits the elimination of several acidic drugs. In this study, the influence of probenecid on the pharmacokinetics of carprofen was investigated in three healthy volunteers after single peroral administration of 150 mg of RS-(+/-)-carprofen. Carprofen enantiomers and their glucuronides (after cleavage with sodium hydroxide) were measured by use of a stereospecific procedure. The plasma concentrations of S-(+)-carprofen were higher than those of R-(-)-carprofen at most of the sampling points. Probenecid reduced apparent total and renal clearances for both enantiomers. It also reduced the clearances of the carprofen enantiomers to their glucuronides and the renal clearances of the glucuronides. The differences caused by probenecid were significant, but few stereoselective effects were observed.

Adult↗

PubMed1991

Muzolimine: renal site of action and interaction with probenecid in humans.

Muzolimine (60 mg, administered orally) was administered to eight healthy volunteers, under conditions of altered fluid load, to elucidate its renal site of action. The duration of action and the effect of probenecid pretreatment on muzolimine response was also investigated. Muzolimine had a rapid onset of action, with the diuresis complete within 4 hours after dosing. At peak natriuresis, under hydrated conditions, fractional excretion of free water remained unaltered (9.72% +/- 0.59% versus 9.07% +/- 0.44%; difference not significant) but was accompanied by a significant increase in the delivery of sodium out of the proximal tubule, as measured by fractional excretion of lithium (22% +/- 2% to 31% +/- 1%; p less than 0.01). The fraction of sodium reabsorbed in the distal tubule also decreased from 94% +/- 1% to 67% +/- 1% (p less than 0.001) of the delivered load. The fractional reabsorption of free water during hydropenia decreased after muzolimine (5.63% +/- 0.26% to 2.00% +/- 0.81%; p less than 0.05). Pretreatment with probenecid resulted in a prominent decrease in urinary sodium excretion (246 +/- 25 mmol/24 hr for muzolimine alone 161 +/- 24 mmol/24 hr for muzolimine and probenecid; p less than 0.01). These findings suggest that muzolimine has a major site of action in the medullary portion of the thick ascending limb of Henle with additional inhibitory activity on the proximal tubule. It is likely that the active secretion of one or more of the acidic metabolites of muzolimine, by way of the probenecid sensitive organic acid pathway, is responsible for mediating the renal actions this basic drug.

Administration, Oral↗

PubMed2000

Effects of endotoxin-induced fever and probenecid on disposition of enrofloxacin and its metabolite ciprofloxacin after intravascular administration of enrofloxacin in goats.

Pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin were investigated in normal, febrile and probenecid-treated adult goats after single intravenous (i.v.) administration of enrofloxacin (5 mg/kg). Pharmacokinetic evaluation of the plasma concentration-time data of enrofloxacin and ciprofloxacin was performed using two- and one-compartment open models, respectively. Plasma enrofloxacin concentrations were significantly higher in febrile (0.75-7 h) and probenecid-treated (5-7 h) goats than in normal goats. The sum of enrofloxacin and ciprofloxacin concentrations in plasma > or =0.1 microg /mL was maintained up to 7 and 8 h in normal and febrile or probenecid-treated goats, respectively. The t1/2beta, AUC, MRT and ClB of enrofloxacin in normal animals were determined to be 1.14 h, 6.71 microg .h/mL, 1.5 h and 807 mL/h/kg, respectively. The fraction of enrofloxacin metabolized to ciprofloxacin was 28.8%. The Cmax., t1/2beta, AUC and MRT of ciprofloxacin in normal goats were 0.45 microg /mL, 1.79 h, 1.84 microg .h/mL and 3.34 h, respectively. As compared with normal goats, the values of t1/2beta (1.83 h), AUC (11.68 microg ? h/mL) and MRT (2.13 h) of enrofloxacin were significantly higher, whereas its ClB (430 mL/h/kg) and metabolite conversion to ciprofloxacin (8.5%) were lower in febrile goats. The Cmax. (0.18 microg /mL) and AUC (0.99 microg .h/mL) of ciprofloxacin were significantly decreased, whereas its t1/2beta (2.75 h) and MRT (4.58 h) were prolonged in febrile than in normal goats. Concomitant administration of probenecid (40 mg/kg, i.v.) with enrofloxacin did not significantly alter any of the pharmacokinetic variables of either enrofloxacin or ciprofloxacin in goats.

Animals↗