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PubMed1990

Ceftriaxone binding to human serum albumin. Indirect displacement by probenecid and diazepam.

In vitro protein binding studies were conducted to examine the interaction between ceftriaxone (CEF), probenecid (PROB) and diazepam (DIAZ). The presence of PROB and DIAZ at concentrations equal to molar albumin concentration caused a decrease in CEF affinity from 3.7 x 10(4) M-1 (control) to 1.1 x 10(4) (PROB) and 2.6 x 10(4) (DIAZ) M-1, but not in binding capacity in pooled human plasma. PROB and DIAZ at five times the molar albumin concentration also caused a decrease in CEF affinity from 4.5 x 10(4) M-1 (control) to 0.45 x 10(4) (PROB) and 3.0 x 10(4) (DIAZ) M-1 in isolated human serum albumin. DIAZ and PROB displaced one another, confirming their common binding site (Site II, the benzodiazepine site) on serum albumin. By contrast, CEF was unable to displace either PROB or DIAZ from defatted albumin. In the presence of elevated free fatty acid concentrations (four times the albumin concentration), CEF decreased the binding of both drugs. CEF free fraction (fp) in isolated human serum albumin (CEF fp = 7.7%) was increased by drugs which bind to Site I: sulfisoxazole (CEF fp = 68.1%), warfarin (CEF fp = 56.0%) and furosemide (CEF fp = 55.0%). At ten times the molar concentration of albumin, CEF displaced both warfarin (warfarin fp from 0.99 to 2.20%) and phenytoin (phenytoin fp from 17.7 to 23.4%) from defatted albumin. CEF appeared to bind to Site I (the warfarin site) on human serum albumin, and was displaced by PROB and DIAZ via a mechanism which did not involve direct competition at a common binding site.

Binding Sites↗
PubMed1991

Modulation of 3'-azido-3'-deoxythymidine catabolism by probenecid and acetaminophen in freshly isolated rat hepatocytes.

Metabolic studies of 3'-azido-3'-deoxythymidine (AZT) in humans have demonstrated that this compound is primarily eliminated as a 5'-O-glucuronide, 3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine (GAZT), accounting for approximately 80% of the administered dose. Recently, we characterized the complete catabolic pathway of AZT in freshly isolated rat hepatocytes in suspension, demonstrating extensive formation of three catabolites, including GAZT, 3'-amino-3'-deoxythymidine (AMT), and 3'-amino-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine (GAMT). The present study evaluated the effects of probenecid (PROB) and acetaminophen (ACET), two agents which are also metabolized by UDP-glucuronyltransferase, on the metabolism and transmembrane distribution of AZT in rat hepatocytes. Pre-exposure of cells to 350 microM PROB 30 min prior to the addition of 10 microM [3H]AZT decreased intracellular GAZT levels by approximately 10-fold. Interestingly, AMT formation was enhanced approximately 1.5-fold in the presence of PROB, probably resulting from increased AZT availability. In contract, pre-exposure to 50 microM ACET 30 min prior to addition of 10 microM [3H]AZT did not substantially alter AZT glucuronidation. Additionally, decreased AZT catabolism by PROB did not contribute to the formation of 5'-phosphorylated derivatives of AZT. Agents which undergo glucuronidation may thus not necessarily affect AZT conversion to GAZT, and their potential interactions should be investigated using in vitro systems prior to co-administration with AZT.

Acetaminophen↗
PubMed1992

Domperidone induces a probenecid-sensitive rise in immunoreactive prolactin in cerebroventricular perfusates in female rats.

The present study examined immunoreactive prolactin (ir-PRL) access into the cerebrospinal fluid (CSF) by monitoring ir-PRL levels in the blood and cerebroventricular perfusates of ovariectomized (ovx) rats treated with the dopamine antagonist, domperidone (DOMP). In Expt. 1 PRL plasma levels were measured in rats treated with DOMP i.p. (2.5, 5.0 and 10.0 mg/kg). All doses of DOMP significantly increased PRL plasma levels. In Expt. 2 animals were treated i.p. with DOMP (10 mg/kg) or DOMP plus the active transport blocking agent, probenecid (PROB; 250 mg/kg). Plasma PRL and ir-PRL in cerebroventricular perfusates were measured in separate sets of animals using catheters and a push-pull perfusion system, respectively. DOMP induced an increase in plasma PRL that was followed 30-40 min later by a rise in ventricular perfusates ir-PRL levels. PROB treatment induced a greater increase in plasma PRL levels in DOMP-treated animals, but delayed the DOMP-induced increase in ir-PRL ventricular perfusate ir-PRL levels. The delay in the rise of ir-PRL in ventricular perfusates observed in rats treated with DOMP plus PROB may be due to a PROB's interference with the transport of PRL from the blood into CSF. These results suggest that under some conditions ir-PRL in CSF originates from the pituitary.

Animals↗
PubMed1975

Host-mediated assay with yeast and rats using probenecid (Benemid) to block the renal tubular excretion of cyclophosphamide metabolites.

The genetic activity of cyclophosphamide (Cy) was tested in the host-mediated assay (injection of yeasts into the peritoneal cavity of rats) modified by the use of probenecid (Pro) (Benemid) to block the renal tubular excretion of the genetically active metabolites. The genetic test system used was the induction of mitotic gene conversion in two unliked loci of a diploid strain of Saccharomyces cerevisiae. By this method the genetic effect of By was doubled in comparison with the case of administering Cy alone. Compared with the animals which received only Pro, increases of conversion frequencies of 20 times in the ade2 locus and of 15 times in the trp5 locus were found.

Animals↗
PubMed1996

Systemic DL-kynurenine and probenecid pretreatment attenuates quinolinic acid-induced neurotoxicity in rats.

Kynurenine (KYN) is the precursor of kynurenic acid (KYNA), an endogenous antagonist of the glycine site of the NMDA (N-methyl-D-aspartate) receptor. Probenecid (PROB), blocks the excretion of KYNA from the extracellular fluid. KYNA antagonizes the toxic action of quinolinic acid (QUIN), an endogenous NMDA receptor agonist. In this study, we tested the effect of the systemic administration of KYN and PROB, either alone or in combination, on QUIN-induced circling behavior and gamma-aminobutyric acid (GABA) depletion in rats. Circling behavior and GABA depletion induced by QUIN were both partially prevented by PROB (200 and 300 mg/kg) and KYN (300 and 450 mg/kg) treatments. Lower doses of drugs administered separately were nonprotective. However, when administered in combination, doses of 150 or 300 mg/kg KYN plus 100 mg/kg PROB significantly protected animals against QUIN neurotoxicity. These findings suggest a role of KYN and PROB as promoters of KYNA-mediated NMDA receptor antagonism, via an increase of kynurenate in brain extracellular spaces.

Animals↗
PubMed1990

Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis.

72 adults with erythema migrans (early Lyme borreliosis) were enrolled in a randomised prospective trial comparing amoxycillin 500 mg plus probenecid 500 mg three times a day with doxycycline 100 mg twice a day for 21 days. These antibiotic regimens were chosen because of the known in-vitro sensitivity of Borrelia burgdorferi, the antibiotic tissue penetration, the pharmacokinetics of the drugs, and because the organism can disseminate early in the course of infection. 72 patients were evaluable (35 in the doxycycline group and 37 in the amoxycillin/probenecid group). The two regimens were equally effective for treatment of erythema migrans. Mild fatigue or arthralgia were the only post-treatment complaints, which resolved within 6 months. None of the patients needed further antibiotic treatment for Lyme borreliosis.

Adult↗
PubMed1989

Measurement of cytoplasmic calcium concentration in cell suspensions: correction for extracellular Fura-2 through use of Mn2+ and probenecid.

1321N1 astrocytoma cells loaded with Fura-2 were found to continuously transport Fura-2 to the extracellular medium. To correct for extracellular Fura-2 fluorescence a protocol was developed in which Mn2+ was added to duplicate cuvettes of cells to quench extracellular Fura-2 at the beginning and end of the experimental time course. Since the export of Fura-2 was linear with time, two separate quench determinations allowed the amount of fluorescence from extracellular Fura-2 fluorescence to be estimated at every point in the time course and subtracted from the data. The uncorrected and Mn2+-corrected basal cytoplasmic calcium concentrations averaged 153 nM and 72 nM, respectively. The peak intracellular calcium concentrations following muscarinic stimulation with 300 microM carbachol averaged 1159 nM (uncorrected) and 889 nM (Mn2+-corrected). Probenecid (2.5 mM) was found to block the export of Fura-2 from these cells and did not change the basal calcium concentration or the muscarinic calcium response.

Astrocytoma↗
PubMed1984

In vivo electrochemical detection of 5-hydroxyindoles in rat cerebral cortex and spinal cord: differential effects of p-chloroamphetamine, probenecid and clorgyline.

Differential pulse voltammetry associated with carbon fiber microelectrodes was used to detect the 300 mV signal which is known to reflect the concentration of 5-hydroxyindoles in the spinal cord and cerebral neocortex of rats anesthetized with urethane or chloral hydrate. The intraperitoneal injection of p-chloroamphetamine resulted in an increase in the amplitude of the signal in the neocortex but not in the spinal cord. Administration of clorgyline did not consistently modify the signal monitored in the neocortex whereas it decreased in the spinal cord. Probenecid induced a larger increase in 5-hydroxyindoles in the neocortex than in the spinal cord. These results demonstrate that different parts of the serotonergic system might be differentially sensitive to drugs affecting serotonin metabolism.

Amphetamines↗
PubMed1992

Direct-gradient high-performance liquid chromatographic analysis and preliminary pharmacokinetics of flumequine and flumequine acyl glucuronide in humans: effect of probenecid.

A gradient high-performance liquid chromatographic analysis for the direct measurement of flumequine, with its acyl glucuronide, in plasma and urine of humans has been developed. In order to prevent hydrolysis and isomerization of flumequine acyl glucuronide, the samples were acidified by the oral intake of four 1.2-g amounts of ammonium chloride per day. In contrast to the acyl glucuronides of non-steroidal anti-inflammatory drugs, flumequine and its acyl glucuronide were stable in urine of pH 5.0-8.0. Flumequine acyl glucuronide is unstable at pH 1.5. In acidic urine (pH 5-6), almost no flumequine is excreted unchanged (1%): it is excreted chiefly as acyl glucuronide (84.2%). Probenecid co-medication reduces the renal excretion rate of flumequine acyl glucuronide from 662 to 447 micrograms/min (p = 0.00080), but not the percentage of glucuronidation.

Anti-Infective Agents↗
PubMed1993

Determination of indomethacin, its metabolites and their glucuronides in human plasma and urine by means of direct gradient high-performance liquid chromatographic analysis. Preliminary pharmacokinetics and effect of probenecid.

Indomethacin is metabolized in humans by O-demethylation, and by acyl glucuronidation to the 1-O-glucuronide. Indomethacin, its metabolite O-desmethylindomethacin (DMI) and their conjugates can be measured directly by gradient high-performance liquid chromatographic analysis without enzymic deglucuronidation. The glucuronide conjugates were isolated by preparative HPLC from human urine samples. In plasma only indomethacin was present. No isoglucuronides were present in acidic urine of the volunteer. The possible metabolite deschlorobenzoylindomethacin (DBI) was not detectable in urine. Calibration curves were constructed by enzymic deconjugation of samples containing different concentrations of isolated indomethacin acyl glucuronide, DMI acyl glucuronide and DMI ether glucuronide. The limit of quantitation of indomethacin in plasma is 0.060 microgram/ml. The limits of quantitation in urine are: indomethacin 0.053 microgram/ml, DMI 0.065 microgram/ml, DMI acyl glucuronide 0.065 microgram/ml and DMI ether glucuronide 0.254 microgram/ml. A pharmacokinetic profile of indomethacin is shown, and some preliminary pharmacokinetic parameters of indomethacin obtained from one human volunteer are given. Probenecid inhibits the formation of both the ether and the acyl glucuronide of DMI.

Chromatography, High Pressure Liquid↗
PubMed1994

Determination of furosemide with its acyl glucuronide in human plasma and urine by means of direct gradient high-performance liquid chromatographic analysis with fluorescence detection. Preliminary pharmacokinetics and effect of probenecid.

Furosemide is metabolized in humans by acyl glucuronidation to the 1-O-glucuronide (Fgluc). Furosemide (F) and the conjugate can be measured directly by gradient high-performance liquid chromatographic analysis without enzymic deglucuronidation. The glucuronide conjugate was isolated by preparative HPLC from human urine samples. Furosemide and its acyl glucuronide were present in plasma. No isoglucuronides were present in acidic urine of a volunteer. Calibration curves were constructed by enzymic deconjugation of samples containing different concentrations of isolated F-acyl glucuronide. The limit of quantitation of F in plasma is 0.007 microgram/ml, Fgluc 0.010 microgram/ml. The limits of quantitation in urine are respectively: F 0.10 microgram/ml, Fgluc 0.15 microgram/ml. A pharmacokinetic profile of furosemide is shown, and some preliminary pharmacokinetic parameters of furosemide obtained from one human volunteer are given. Probenecid does not inhibit the formation of the acyl glucuronide of F, but inhibits the renal clearance of both compounds.

Chromatography, High Pressure Liquid↗
PubMed1987

Rapid and sensitive method for measuring norepinephrine, dopamine, 5-hydroxytryptamine and their major metabolites in rat brain by high-performance liquid chromatography. Differential effect of probenecid, haloperidol and yohimbine on the concentrations of biogenic amines and metabolites in various regions of rat brain.

A rapid and sensitive method has been developed for the simultaneous determination of norepinephrine, dopamine, 5-hydroxytryptamine and their respectively metabolites 3-methoxy-4-hydroxyphenylglycol, homovanillic acid, 3,4-dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid in discrete brain regions of rats. The supernatants of tissue homogenates were injected directly into a reversed-phase liquid chromatography system, coupled with electrochemical detection. Each of these compounds gave a linear response over the range 5.5-200 ng/ml cerebellar homogenate (0.11-4.0 ng on column). Analytical recoveries of these compounds, added to the homogenate, were essentially complete when compared with standards dissolved in perchloric acid. The average between-assay coefficients of variation for all these compounds were lower than 6.9% over the range 5.5-200 ng/ml. The within-assay coefficients of variation were lower than 9.7%, measured at 5.5 or 23.6 ng/ml. With the present test parameters and mobile phase conditions, all compounds were readily oxidized at 0.8 V vs. a Ag/AgCl reference electrode. The method was applied to an analysis of the differential activity of biogenic amines in the rat striatum, hypothalamus, and hippocampus, produced by probenecid, haloperidol and yohimbine.

Animals↗
PubMed1990

The use of probenecid to increase the serum amoxycillin levels in patients with bronchiectasis.

Amoxycillin 3 g twice daily is effective in treating patients with bronchiectasis who have daily purulent sputum. However, it is a relatively expensive treatment if used for prolonged periods. This pilot study in six patients with bronchiectasis showed that the concurrent administration of probenecid with a smaller dose of amoxycillin produced similar clinical responses and pharmacokinetic profiles to those found with high dose amoxycillin alone. The amount of amoxycillin used was reduced by two thirds, producing a potential saving of approximately pound 1000 per patient per annum in those taking long term treatment.

Adult↗
PubMed1998

Cyclic AMP stimulates the cyclic GMP egression pump in human erythrocytes: effects of probenecid, verapamil, progesterone, theophylline, IBMX, forskolin, and cyclic AMP on cyclic GMP uptake and association to inside-out vesicles.

The knowledge about the structure and function of the protein families responsible for cGMP synthesis and metabolic conversion has grown vastly the last years, whereas little is known about proteins that account for the cellular export of cGMP. In the present study, we have employed a model with inside-out vesicles prepared from human erythrocytes to characterize modulation and regulation of cellular cGMP extrusion. The active transport was saturable (Km of 2.4 +/- 0.2 microM, mean +/- SEM, n = 3) and coupled to ATP hydrolysis since no accumulation was detected in the presence of ATP-gamma-S and AMP-PNP. The observation that 100 microM of cAMP caused a minimal inhibition (14.4 +/- 0.3%) of active cGMP transport showed that the extrusion system for cGMP was not shared with cAMP, but a competitive interaction occurred for the ATP-independent association to the inside out vesicles. In contrast, the lowest, but physiological relevant cAMP concentrations (0.1-5 microM) stimulated the active cGMP transport with 30-35%, an observation that suggests cAMP as an allosteric regulator of the cGMP transporter. Several well-known modulators of other energy-requiring membrane transport systems caused a competitive and concentration-dependent inhibition, including verapamil (Ki = 13.0 +/- 2.4 microM), forskolin (Ki = 13.5 +/- 1.4 microM) and probenecid (Ki = 27.0 +/- 1.3 microM). Progesterone, which was the most potent inhibitor (Ki = 2.2 +/- 0.3 microM), interacted with the active cGMP transport in a noncompetitive manner. The highest concentration (100 microM) of IBMX and theophylline reduced the active cGMP uptake with 29.5 +/- 1.9% and 21.6 +/- 2.1%, respectively. None of these substances interfered with the association of cGMP to the vesicles in absence of ATP. The present results show that human erythrocytes possess a cell membrane cGMP transporter which is coupled to an ATPase. Its activity is regulated by cAMP in an apparent allosteric manner and inhibited by substances previously known to interact with other membrane transport systems.

1-Methyl-3-isobutylxanthine↗
PubMed1997

Zidovudine transport within the rabbit brain during intracerebroventricular administration and the effect of probenecid.

The elimination of zidovudine (AZT) from cerebrospinal fluid (CSF), its distribution from CSF to brain tissue, and its transport from brain extracellular fluid (ECF) to plasma were studied during intracerebroventricular (i.c.v.) infusion in unanesthetized rabbits. The effect of probenecid (PBD) on these transport processes was also studied. The concentration of AZT in brain ECF was measured by microdialysis with retrodialysis calibration for in vivo recovery. Plasma and CSF were sampled and analyzed for AZT and PBD using HPLC. The elimination of AZT from CSF showed nonlinear characteristics as the i.c.v. infusion rate was increased to 1 mg/h kg. The estimated maximum transport capacity and dissociation constant were 3.5 micrograms/min kg and 127 micrograms/mL, respectively. The total linear elimination clearance from CSF was 0.0073 mL/min kg. The spatial distribution of AZT in brain during i.c.v. infusion was simulated using a mathematical model which describes diffusive solute transport in brain ECF and efflux across the blood-brain barrier. This analysis yielded a brain to plasma efflux rate constant of 0.040/min. This parameter and the elimination clearance from CSF decreased significantly by the end of an 8-hour period during which PBD was infused intravenously at a rate of 15 mg/h kg.

Animals↗
PubMed1979

[Cross allergy between sulphonamide diuretics, probenecid, sulphamethoxazole and sulphonyl-urea compounds (author's transl)].

Typical signs and symptoms of type III allergy occurred in a 55-year-old diabetic during diabetes and diuretic treatment with glisoxepid, glibenclamide, furosemide and probenecid. Symptoms of this type of allergy unintentionally recurred with every subsequent therapeutic administration of each one of these drugs. The possibility of a cross allergy between sulphonamide diuretics, chemotherapeutic sulphonamides and sulphonyl-urea compounds has only rarely been described.

Cross Reactions↗
PubMedDate not supplied

Probenecid, sulfinpyrazone and pyrazinamide do not inhibit urinary excretion of the beta 2-adrenoceptor agonist clenbuterol in cattle.

The objective of this study was to develop an analytical approach to determine whether the illegal application of clenbuterol in cattle as an anabolic agent can be concealed by co-treatment with substances that affect urinary excretion. Female veal calves were dosed orally with 0.8 microgram clenbuterol per kg of body weight twice daily for 28 days, as licensed for the therapeutic use which is registered in most European countries. On the eighth day of clenbuterol treatment each calf was additionally dosed orally either with probenecid, sulfinpyrazone or pyrazinamide at three different doses that were increased in weekly intervals. During the treatment blood and urine samples were obtained and analysed for clenbuterol by enzyme immunoassay and by high performance liquid chromatography/ enzyme immunoassay to determine whether these drugs or their metabolites interfered with the immunological detection of clenbuterol. Clenbuterol could be in plasma (approximately 200 pg ml-1) and urine (1-40 ng ml-1) 5 h after the initial intake and throughout the whole treatment. None of the drugs reduced urinary excretion of clenbuterol to concentrations below the limit of detection. There was no prevention of clenbuterol detection in urine samples from calves that were co-treated with the drugs tested in this study. Our results demonstrate the uselessness of applying these drugs in order to conceal the illegal use of clenbuterol in meat production.

Administration, Oral↗
PubMed1987

Ciprofloxacin versus ampicillin and probenecid in the treatment of uncomplicated gonorrhoea in men.

Eighty-six men with uncomplicated gonorrhoea were entered into a study comparing the efficacy of a single oral dose of 250 mg of ciprofloxacin with a single oral dose of ampicillin 2 g and probenecid 1 g for urethral gonorrhoea and a course of ampicillin, 500 mg four times per day for five days in rectal and pharyngeal infection. Two patients were excluded. Of the remaining 84, 45 were treated with ampicillin and 39 with ciprofloxacin. In the ampicillin group there were two treatment failures out of 40 urethral infections. Three patients with rectal infection were cured. Only one patient out of three pharyngeal infections was cured. Ciprofloxacin cured all of 34 urethral and three rectal infections including one penicillinase producing strain of Neisseria gonorrhoeae (PPNG). Four of five pharyngeal infections were cured but there was one treatment failure. There were no major side effects in either treatment group. In conclusion, a single oral dose of 250 mg of ciprofloxacin is an effective treatment for uncomplicated gonorrhoea in men.

Ampicillin↗