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PubMed1997

Quantitative evaluation of brain distribution and blood-brain barrier efflux transport of probenecid in rats by microdialysis: possible involvement of the monocarboxylic acid transport system.

This study was performed to evaluate quantitatively the brain distribution and the efflux transport across the blood-brain barrier of probenecid, using in vivo microdialysis and in situ brain perfusion techniques. The brain interstitial fluid (ISF)-to-plasma cerebrospinal fluid (CSF)-to-plasma and brain tissue-to-plasma unbound concentration ratios of probenecid at steady state were less than unity, which suggests restricted distribution in the brain. An uphill concentration gradient from ISF to plasma and a downhill concentration gradient from CSF to ISF were observed. Kinetic analysis revealed that the efflux clearance from brain ISF to plasma (0.0373 ml/min/g brain) was significantly greater than the influx clearance from plasma to brain (0.00733 ml/min/g brain). The ratio of the ISF concentration (Cisf) to the plasma unbound concentration (Cp,f) of probenecid was increased 2- to 3-fold by salicylate (3.7 mM) and benzoate (3.6 mM), which are accepted as substrates of the monocarboxylic acid transport system, compared with the same ratio for the control. In addition, the ratio Cisf/Cp,f was increased by treatment with N-ethylmaleimide, a sulfhydryl-modifying agent, whereas p-aminohippuric acid and choline did not produce increasing effects on Cisf/Cp,f. These data suggest that the restricted distribution of probenecid in the brain may be ascribed to efficient efflux from the brain ISF, which may be regulated by the monocarboxylic acid transport system at a relatively high ISF concentration.

Animals↗
PubMed1991

The use of probenecid as a chemoprotector against cisplatin nephrotoxicity.

Probenecid inhibits cisplatin (CP) secretion in humans and protects against CP-induced nephrotoxicity in rats. The authors conducted a Phase I trial of escalating doses of CP using probenecid as a chemoprotector. Fifty-four courses of CP at doses ranging from 100 to 160 mg/m2 were given by 24-hour infusion to 36 patients. There was no renal impairment at any dose. Ototoxicity, however, became the dose-limiting toxicity; 14 patients experienced a 20 or greater decibel (dB) loss. Seven percent of courses were associated with a leukocyte count of less than 1.5 x 10/microliters, and 19% with a platelet count of less than 50 x 10(3)/microliters. Only three patients developed neurotoxicity. Correlating pharmacokinetic data and toxicity, the authors found that high cumulative dose, area under the curve (AUC) for unbound platinum, and cumulative AUC were associated with ototoxicity and peripheral neuropathy. It was concluded that probenecid may protect against CP nephrotoxicity and warrants further investigation. Its unique mechanism of action and lack of toxicity make it ideal to combine with other chemoprotectors.

Adult↗
PubMed1992

Influence of probenecid and paracetamol (acetaminophen) on zidovudine glucuronidation in human liver in vitro.

The effects of probenecid and paracetamol on zidovudine glucuronidation were investigated, in vitro, using human liver microsomal preparations. The presence of probenecid in the incubation medium significantly reduced the maximum reaction velocity for zidovudine glucuronide formation by more than 60 per cent, and the Km was reduced by 47 per cent, suggesting an uncompetitive inhibition of zidovudine glucuronidation. In contrast, paracetamol had no significant effect on zidovudine glucuronidation. The maximum reaction velocity for zidovudine glucuronide formation and the Km were unchanged when paracetamol (5 mM) was present in the incubation medium. The effects of probenecid and paracetamol on zidovudine metabolism in vitro correlates closely with those observed in vivo. The in vitro system of human liver microsomes may have a useful role in predicting the possible interaction of other drugs with zidovudine metabolism.

Acetaminophen↗
PubMed2002

Disposition of acamprosate in the rat: influence of probenecid.

The purpose of the present study was to investigate the disposition of acamprosate (calcium bis acetyl-homotaurine) in the rat. Initially, we studied the linearity of acamprosate disposition and the fraction of acamprosate excreted unchanged in the urine of the animals. Rats received 9.3, 36.6 or 73.3 mg/kg of the drug as an intravenous bolus. The statistical analysis of the pharmacokinetic parameters did not reveal any significant difference, indicating that acamprosate disposition was linear within the range of the doses assayed. On average, 95% of the administered dose was excreted unchanged in the urine of the animals in the 0-6 h post-administration period indicating that renal excretion is the main elimination route for this drug. Acamprosate was also administered by the intravenous route at three different constant infusion rates (2.65, 132.5 and 530 microg/min) in order to quantify total (Cl(t)) and renal (Cl(r)) plasma clearances at steady-state conditions. The mean Cl(r) values were, respectively, 4.60+/-0.42, 4.28+/-0.52 and 4.08+/-0.67 ml/min, practically equivalent to the Cl(t) values (4.78+/-0.38, 4.51+/-0.36 and 4.21+/-0.56 ml/min), confirming that the drug is mainly eliminated via renal excretion. Moreover, Cl(r) values were clearly higher than the glomerular filtration rate (2.61+/-0.26 ml/min), suggesting the existence of a highly efficient tubular secretion mechanism in the renal excretion of the drug. To confirm this hypothesis, two groups of rats were intravenously treated with probenecid (33.3 or 66.6 mg/kg) prior to acamprosate administration (9.3 mg/kg). Probenecid provoked a statistically significant dose-dependent reduction in the total clearance of acamprosate (from 5.8+/-0.7 ml/min in the control group to 2.6+/-0.1 ml/min in the animals treated with 66 mg/kg of probenecid) demonstrating the existence of a tubular secretion process on the renal excretion of acamprosate in the rat.

Acamprosate↗
PubMed1995

On the relationship between the probenecid-sensitive transport of daunorubicin or calcein and the glutathione status of cells overexpressing the multidrug resistance-associated protein (MRP).

Cells exposed to calcein acetoxymethyl ester (calcein AM) in the growth medium become fluorescent following cleavage of calcein AM by cellular esterases to produce the fluorescent derivative calcein. It has previously been shown by others that multidrug resistant cells which overexpress P-glycoprotein accumulate much less fluorescent calcein than the corresponding parental cells. We have now examined the transport of calcein in multidrug resistant cells which overexpress an alternative transporter, the multidrug resistance-associated protein (MRP). Accumulation of calcein fluorescence was greatly reduced in the MRP-overexpressing human lung cancer cell lines COR-L23/R and MOR/R compared with their parental lines. Energy depletion resulted in a considerably increased accumulation in the resistant lines. Treatment of resistant cells with buthionine sulfoximine (BSO), which depletes cellular glutathione (GSH), did not affect calcein accumulation, in marked contrast to our previous results for daunorubicin or the fluorescent probe rhodamine 123. Genistein, verapamil, cyclosporin A and ouabain were also each able to modify, to some extent, accumulation of daunorubicin, whilst having essentially no effect on calcein accumulation. However, the organic anion transport inhibitor probenecid was able to increase accumulation of both calcein and daunorubicin in the resistant cells. Genistein and verapamil treatment preferentially reduced the GSH content of resistant cells, whilst probenecid did not. However, probenecid caused a clear decrease in release of GSH from resistant cells into the medium.

ATP-Binding Cassette Transporters↗
PubMed1981

Effect of probenecid on response to bumetanide in man.

We administered 0.5-and 1.0-mg doses of bumetanide intravenously to eight normal subjects with and without pretreatment with probenecid. Probenecid did not effect either the cumulative response or the time course of response of bumetanide. These results are in contrast to results reported in dogs but consistent with similar studies in cats. The data imply that probenecid and potentially other exogenous or endogenous organic acids do not affect the renal handling of bumetanide in normal man.

Adult↗
PubMedDate not supplied

Interaction studies with bumetanide and furosemide. Effects of probenecid and of indomethacin on response to bumetanide in man.

Bumetanide was administered intravenously in doses of 0.5 and 1.0 mg to eight normal subjects with and without pretreatment with probenecid or indomethacin. Probenecid did not affect either the cumulative response or the time course of response to bumetanide. This may mean that probenecid and potentially other exogenous or endogenous organic acids do not affect the renal handling of bumetanide in normal man. Indomethacin pretreatment decreased the cumulative 4-hour excretion of sodium caused by 1.0 mg bumetanide from 276 +/- 22.9 to 202 +/- 20.9 mEq (P less than 0.003). Effects on volume and chloride paralleled those of sodium, while potassium excretion was not affected. When the response was analyzed as increment in fractional excretion over basal solute excretion, determined from separate control studies, indomethacin still decreased the response, possibly indicating that endogenous prostaglandins may play a role in determining the overall response to bumetanide.

Adult↗
PubMedDate not supplied

Effect of probenecid on the natriuresis and renin release induced by bumetanide in man.

In a randomized crossover trial in six normal male subjects, the effect of pretreatment with probenecid on natriuresis and renin release in response to bumetanide was studied. The subjects received 120 mEq sodium and 80 mEq potassium per day. A single dose of 2 mg bumetanide was administered on the fourth morning after pretreatment with either placebo or probenecid. Creatinine and uric acid were measured in serum and urine, plasma renin activity was determined by radioimmunoassay of angiotensin I, and plasma and urine concentrations of bumetanide were measured by a highly sensitive radioimmunoassay method. Probenecid reduced both natriuresis and hyperreninemia induced by bumetanide. This effect is postulated to be due not to a direct action on sodium excretion but is probably secondary to inhibition of renal tubular secretion of bumetanide. Consequently, these findings appear to support the concept that the quantity of bumetanide delivered to the tubular lumen is an important determinant of its diuretic effect.

Adult↗
PubMed1992

Pharmacokinetic interactions of cefprozil with food, propantheline, metoclopramide, and probenecid in healthy volunteers.

Cefprozil, a new oral cephalosporin antibiotic, is composed of cis and trans isomers in an approximate 90:10 ratio. The objectives of this study were: (1) to assess the effects of alterations in gastrointestinal motility by metoclopramide and propantheline on the pharmacokinetics of cis and trans isomers of cefprozil, and to compare them with the effects of food on the pharmacokinetics of cefprozil; (2) to assess the effects of inhibition of renal tubular secretion by probenecid on the pharmacokinetics of cefprozil isomers. In this four-way crossover study, 15 healthy male volunteers received a 1000-mg dose of cefprozil after fasting, pretreatment with metoclopramide or propantheline, after breakfast, or after probenecid in an incomplete, balanced block design. There was a 1-week washout period between each treatment. Blood and urine samples collected over a 24-hour period were assayed for the cis and trans isomers. The concentrations of the trans isomers were generally 1/10 of the cis isomer. The means and variances of the pharmacokinetic parameters of the cis and trans isomers of cefprozil were similar in fasting subjects and were affected in a parallel manner by food, metoclopramide, propantheline, and probenecid. The pharmacokinetics of the cis isomer under the fasting condition were as follows: maximum peak plasma concentration (Cmax), 14.0 +/- 2.7 micrograms/mL; median time to reach Cmax (tmax), 1.5 (range, 1.0-3.5) hours; half-life (t1/2), 1.24 +/- 0.27 hours; area under the concentration (AUC0-infinity), 47.3 +/- 7.7 micrograms.hour/mL; mean residence time after oral administration (MRTpo), 2.9 +/- 0.4 hours; CLR, 219 +/- 60 mL/minute; and Xu% (percent cumulative urinary excretion in 0-24 hours), 68.1 +/- 12.5.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Evidence for probenecid-sensitive organic anion transporters on polarized thyroid cells in culture.

Epithelial thyroid cells in primary cultures loaded with BCECF/AM rapidly released the impermeant fluorescent dye BCECF (bis(carboxyethyl)carboxyfluorescein) in the incubation medium. Cells organized into follicles rapidly cleared BCECF (80% within 10 min) whereas fluorescence microscopy did not show any fluorescence in the follicular cavity. Cells organized into monolayers on plastic exported BCECF into the medium (70% within 40 min) whereas fluorescence microscopy showed intense fluorescence under the domes. BCECF efflux was blocked by probenecid, one of the known inhibitors of organic anion transporters, with similar efficiency in both structures. Maximal and half-maximal effects were respectively observed for 5 mM and 0.4 mM probenecid. The polarity of BCECF efflux was studied by using monolayers on collagen-coated Nuclepore filters: 85% of BCECF released was found in the basal compartment and 15% in the apical compartment. These findings suggested that thyroid cells in culture expressed a transport mechanism for the anionic form of BCECF. Furthermore, the observed activation of the Na+/H+ exchanger by probenecid suggested that the presence of this blocker did not overcome problems arising in the use of BCECF as intracellular pH indicator for thyroid cells.

Ammonium Chloride↗
PubMed1980

Preliminary evaluation of furosemide-probenecid interaction in humans.

The pharmacokinetics and pharmacodynamics of intravenous furosemide, 40 mg, were studied in four healthy male subjects in a crossover fashion with and without probenecid pretreatment. In each study, 16 plasma and 10 urine samples were collected over 24 hr. Fluid and electrolyte urinary losses were replaced orally throughout the study. Unchanged furosemide and probenecid were measured using high-pressure liquid chromatography; urinary sodium was measured by flame photometry. Although probenecid caused marked changes in the pharmacokinetic parameters of furosemide (increased area under the curve, decreased plasma and renal clearance, increased half-life, and decreased fraction excreted unchanged in the urine), there was no significant difference in its gross 8-hr natriuretic and diuretic effect. However, analysis of the time course of natriuresis showed a pattern similar to that of the urinary furosemide excretion rate, whereas the plasma concentration was poorly correlated over the entire dose-response curve.

Adult↗
PubMed1980

Negligible excretion of unchanged ketoprofen, naproxen, and probenecid in urine.

On the average, 0.6% of a dose of ketoprofen or naproxen or 1.2% of a dose of probenecid was found in the urine of normal male volunteers assayed immediately after its collection. Between approximately 60 and 85% of the dose of these drugs can be excreted in the urine as conjugates, which rapidly hydrolyze at body temperature, at room temperature, and even during frozen storage, thereby regenerating the parent drug. Since urine collections involved sample retention in the bladder at 37 degrees for collection intervals as long as 2--3 hr, the given percentages excreted unchanged probably are overestimates. It is possible that no unchanged ketoprofen, naproxen, or probenecid is excreted in urine. This study contrasts with previous reports of up to 50% of a dose of ketoprofen and 15--17% of doses of naproxen and probenecid being excreted in urine as the parent compound. Those reports probably reflect primarily the duration of frozen sample storage between collection and assay along with the urine collection schedules employed the speed of the clinical procedures, and the analytical procedures used. Attention should be given to potential conjugate hydrolysis whenever the pharmacokinetics of carboxylic acids are studied.

Humans↗
PubMed1986

Effects of 5,8-dideazaisopteroylglutamate (IAHQ) on L1210 leukemia in mice when given alone and in combination with methotrexate, probenecid, or verapamil.

The folate analogue 5,8-dideazaisopteroylglutamate (IAHQ; NSC-289517) inhibits the growth of a variety of human tumor cells in vitro such as colon, breast and osteosarcoma. Since IAHQ has only modest activity against L1210 leukemia in mice, it was tested in combination with methotrexate (MTX), probenecid, or verapamil in an effort to enhance efficacy. Single drug or drug combinations were administered every other day 3 or 5 times beginning on day 1 following the administration of 10(6) L1210 cells per animal. The combination of IAHQ (100 mg/kg) plus MTX (10 mg/kg) produced a decrease in mean survival time compared to that of MTX alone, regardless of whether the drugs were initiated on the same day or whether either one was started 2 days prior to the other. IAHQ (150 mg/kg) plus verapamil (5, 10, or 20 mg/kg) did not alter significantly the results produced by IAHQ alone. However, the combination of IAHQ (150 mg/kg) plus probenecid (250 mg/kg) augmented the increase in mean survival time above that produced by IAHQ alone by 82% (p = less than 0.001). The results suggest that probenecid could be used to enhance the effectiveness of IAHQ against solid tumors such as colon adenocarcinoma.

Animals↗
PubMed1989

Dichlorovinyl cysteine (DCVC) in the mouse kidney: tissue-binding and toxicity after glutathione depletion and probenecid treatment.

The kidney binding of dichloro[14C]vinyl cysteine (14C-DCVC, 8 mg/kg body wt) and the kidney histopathology of DCVC (5 mg/kg body wt) were examined and compared in female C57BL mice subjected to various treatments. To evaluate the roles of organic anion transport and glutathione (GSH) status, mice were pretreated with probenecid (inhibitor of organic anion transport), L-buthionine-S,R-sulfoximine (BSO; inhibitor of GSH synthesis) or with diethyl maleate (DEM; GSH-depleting agent). In addition, the sites of 14C-DCVC binding in BSO-treated and control mice were monitored by microautoradiography. Probenecid was found to inhibit both kidney binding and toxicity of DCVC. In BSO-treated mice, DCVC binding remained roughly unchanged, whereas nephrotoxicity was severely increased and topographically extended to the subcapsular region. Microautoradiography showed that the site of DCVC binding in the straight portion of the proximal tubule was not changed by BSO. In DEM-treated mice, a clearly decreased DCVC binding was observed, while the effect on nephrotoxicity was minute. The effects of probenecid on DCVC binding and toxicity support a role for carrier-mediated transport of DCVC equivalents into the target cells. The BSO result suggests a protective function of GSH towards the nephrotoxicity of DCVC. Moreover, they support our previous contention that a primary lesion occurs at the site of DCVC binding, followed by a secondary, dose-dependent lesion localized outside the DCVC-binding region. In the case of DEM it is proposed that a DEM-GSH conjugate might compete for the uptake and/or activation of DCVC in the target cells.

Animals↗
PubMed1990

The effects of frusemide and probenecid on the pharmacokinetics of phenprocoumon.

We have studied the pharmacokinetics of phenprocoumon with and without co-administration of frusemide and probenecid in two groups of 17 healthy volunteers. Frusemide 40 mg b.i.d. for 7 days did not interact with phenprocoumon to a significant extent. Probenecid 500 mg q.i.d. for 7 days significantly accelerated the overall elimination of phenprocoumon, as indicated by a decrease in AUC from 295 to 157 micrograms.h.ml-1, and a reduction in the fraction of the dose excreted by the kidneys. The data are consistent with inhibition of the glucuronidation of phenprocoumon by probenecid. Its accelerated elimination may be a consequence of the increased formation of hydroxylated metabolites.

Administration, Oral↗
PubMed1993

The effect of probenecid on paracetamol metabolism and pharmacokinetics.

The influence of probenecid on the pharmacokinetics of paracetamol was investigated in a group of healthy volunteers. Pretreatment with probenecid caused a significant decrease in paracetamol clearance (6.23 to 3.42 ml.min-1.kg-1). The urinary excretion of paracetamol sulphate (243 to 193 mg); and paracetamol glucuronide (348 to 74.5 mg) were significantly reduced, whereas that of paracetamol was unchanged. Probenecid was shown to be an uncompetitive inhibitor of paracetamol glucuronidation in vitro, using rat liver microsomes.

Acetaminophen↗
PubMed1979

Cerebrospinal fluid cyclic AMP and acid monoamine metabolites following probenecid: studies in psychiatric patients.

At probenecid levels greater than 10 microgram/ml, CSF cAMP was independent of CSF probenecid concentration. At these levels of probenecid, cAMP transport out of CSF is probably maximally blocked and cAMP levels reflect cAMP release into CSF. CSF cAMP was significantly higher in RDC-diagnosed schizophrenics than in other psychotics or depressives. A significant decrease in CSF cAMP was found in psychotic patients treated with chlorpromazine, No changes in CSF cAMP were observed in patients treated with tricyclic antidepressants or lithium.

Adolescent↗
PubMed1977

Evidence for a probenecid-sensitive transport system of acid monoamine metabolites from the spinal subarachnoid space.

The location of probenecid-sensitive elimination mechanisms of monoamine metabolites from the cerebrospinal fluid of the cat was determined with ventriculo-cisternal or ventriculo-lumbar perfusion techniques. These techniques were described in detail. Levels of endogenous homovanillic acid and 5-hydroxyindoleacetic acid were assayed in the perfusate. Probenecid administration induced the most marked increase of the levels of the monoamine metabolites in the ventriculo-lumbar perfusates. It was concluded that probenecid blocked the transport of both metabolites from the spinal subarachnoid space.

Animals↗