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PubMedDate not supplied

Evaluation of treatment with single-dose ampicillin/sulbactam with probenecid or ceftriaxone in patients with uncomplicated gonorrhea.

This study compared ampicillin/sulbactam plus probenecid with ceftriaxone for treatment of uncomplicated gonorrhea. Of the 297 men and women who were enrolled and randomized to receive either ampicillin/sulbactam (1.0 g/0.5 g) with probenecid (1 g) or ceftriaxone (0.25 g), 274 patients were evaluable. Both ampicillin/sulbactam and ceftriaxone were administered by intramuscular injections. Patients were gonococcal contacts, had positive culture results for Neisseria gonorrhoeae, or had clinical evidence of gonorrhea. Specimens for gonococcal cultures were collected from the cervix (female patients), urethra, rectum, and pharynx at pretreatment and test-of-cure visits. The presence of N. gonorrhoeae and a test-of-cure visit were required for drug efficacy analysis. Of the 274 evaluable patients, 195 (71.2%) had positive culture results for N. gonorrhoeae. Cure was achieved in 93 (94.9%) of 98 patients receiving ampicillin/sulbactam with probenecid and in 96 (99.0%) of 97 patients receiving ceftriaxone. Penicillinase-producing N. gonorrhoeae strains were found in 21 (10.8%) patients; these were eradicated by either ampicillin/sulbactam with probenecid (N = 9) or ceftriaxone (N = 12). Overall, the two drug regimens were very well tolerated and no serious adverse effects were noted. Ampicillin/sulbactam with probenecid may be useful as single-dose therapy in patients with uncomplicated genitorectal gonorrhea.

Adolescent↗
PubMed1992

Diuretic and non-diuretic actions of furosemide: effects of probenecid.

Furosemide causes not only natriuresis, but a rapid (5-10 min) increase in plasma renin activity. The latter has been attributed both to the release of eicosanoids from renal blood vessels and to changes in sodium delivery to the macula densa. Drugs like indomethacin abolish the renin increment and could potentially affect both mechanisms: they inhibit cyclooxygenase but could also compete with furosemide for transport into the tubular lumen, reducing furosemide concentration at its site of action. We studied the effects of probenecid, a weak acid without cyclooxygenase activity, on the responses to furosemide in 20 healthy young men. Each received placebo and low (1000 mg/d) or high (2000 mg/d) doses of probenecid for one week in double-blind, randomized trials, crossover fashion. One hour after the last dose, all participants were given furosemide 0.5 mg/kg intravenously. Probenecid reduced serum uric acid in a dose-dependent manner but did not change platelet thromboxane B2 production. Similarly, there was no change in urine excretion rates of thromboxane B2 or 6ketoprostaglandin F1 alpha, or in baseline or stimulated plasma renin activity. The total natriuresis in 4 h was also unchanged. By contrast, the sodium excretion rate in the first 30 min was reduced after both probenecid regimens while that of later periods was increased. These findings are consistent with the proposed effect of probenecid as reducing furosemide secretion in the proximal tubule, which reduces its concentration at the lumenal surface of the thick ascending limb of Henle's loop, but also prevents its excretion from the body.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Comparative effects of rifampin and/or probenecid on the pharmacokinetics of temazepam and nitrazepam.

The pharmacokinetics of nitrazepam and temazepam were investigated in 16 healthy volunteers before and after seven days of the administration of rifampin 600 mg/d and/or probenecid 500 mg/d. In order to determine the endoplasmatic reticulum enzyme function, 6-beta-hydroxycortisol excretion and antipyrine pharmacokinetic parameters were evaluated. After the administration of rifampin, the total body clearance of antipyrine and nitrazepam increased by 87% and 83%, respectively. After the combined treatment with rifampin and probenecid, the elimination of the two drugs was also increased, even though to a lesser extent (33%, 31%). After the administration of probenecid only, the total clearances of antipyrine and nitrazepam were decreased by 22% and 25%, respectively. The urinary clearance of the antipyrine metabolites also decreased. In norantipyrine and 4-OH-antipyrine, this was due to a significant reduction of glucuronide fraction (211 +/- 32 to 159 +/- 26 mg, and 259 +/- 39 to 191 +/- 25 mg). The sulphate fraction of norantipyrine increased by 18% and that of 4-OH-antipyrine by 21%. Apart from a reduced excretion of the glucuronide fraction, the pharmacokinetics of temazepam were neither altered significantly by probenecid nor by rifampin. According to the outcome of this investigation, probenecid seems to bring about not merely an inhibition of phase II but also an inhibition of phase I metabolization.

17-Hydroxycorticosteroids↗
PubMed1990

Renal responses and pharmacokinetics of piretanide in humans: effect of route of administration, state of hydration and probenecid pretreatment.

The influence of route of administration, state of hydration and transport inhibitor probenecid on the renal responses of a loop diuretic, piretanide, were investigated in 14 healthy volunteers. Maximally achieved plasma concentrations after i.v. and oral piretanide were higher in the nonhydrated state [+54% (i.v.); + 68% (oral)], accompanied by significant decreases in mean residence time, renal clearance and fraction of unchanged drug excreted with nonsignificant decreases in t1/2, steady-state volume of distribution and total clearance when compared with the hydrated state. Relative differences between the two hydrated states in maximal plasma concentrations of piretanide remained after probenecid [+26% (i.v.); +55% (oral)] but changes in kinetic parameters did not. Pretreatment with probenecid produced significant increases in absolute peak and plasma diuretic concentrations, t1/2 and mean residence time while decreasing steady-state volume of distribution, total clearance, renal clearance and fraction of unchanged drug excreted without affecting the bioavailability of piretanide. Urinary drug recovery was greater after i.v. than after oral piretanide, the recovery being consistently lower in nonhydrated state [iv: 2.78 (nonhydrated) versus 3.41 mg/24 h (hydrated); oral: 1.93 (nonhydrated) versus 2.76 mg/24 h (hydrated)]. Probenecid pretreatment reduced the overall urinary recovery of piretanide without altering the i.v./oral differences. Excretion of sodium paralleled piretanide excretion throughout the study except after i.v. dosing in the nonhydrated state where changes in drug excretion after probenecid (2.55 versus 1.63 mg/6 h) failed to influence sodium output (167 versus 152 mmol/6 h). These results demonstrate the importance of route of administration and state of hydration in determining the pharmacocological response of loop diuretics within the kidney.

Administration, Oral↗
PubMed1977

The effects of probenecid upon the individual components of indomethacin elimination.

The effects of probenecid upon plasma profiles for indomethacin and upon the individual components of total plasma clearance have been evaluated in dogs, monkeys and rats. These three species cover the wide spectrum of species differences with respect to the relative contribution of renal, biliary and metabolic clearances to elimination of indomethacin. In dogs, in which biliary clearance is the major component of elimination, probenecid raised incremental values for area under the plasma curve [AUC] greater than 2-fold and completely obliterated the normal portal: peripheral gradient of drug after i.v. dosage. Biliary clearance, measured directly, was inhibited 70%. In rats, in which metabolic clearance is predominant, probenecid had no significant effect upon plasma clearance. In rhesus and spider monkeys, in which renal, metabolic and biliary clearances are all significant, as in man, areas under the plasma curve for indomethacin were more than doubled by probenecid, concomitant with profound depressions of both renal and biliary clearances. If plasma levels are a valid index of pharmacological availabiltiy and amount of drug secreted in bile a correlate of intestinal irritation, probenecid increases therapeutic ratio with respect to intestinal toxicity ca. 5-fold in spider monkeys and 10-fold in rhesus monkeys.

Animals↗
PubMed1979

Reduction of the renal toxicity of cis-dichlorodiammineplatinum(II) by probenecid.

Probenecid, when administered sc to F344 rats 1 hour prior to an iv LD50 dose of cis-dichlorodiammineplatinum(II) (CDPP), reduced significantly the peak BUN and serum creatinine levels which occurred 4 days following CDDP. Renal histopathology was similarly reduced by probenecid pretreatment. In BDF, mice, the LD50 value of CDDP administered ip without probenecid pretreatment was 17 mg/kg; the LD50 dose with probenecid was increased to greater than 19 mg/kg. Probenecid pretreatment did not influence the therapeutic response to CDDP when the letter was administered to BDF mice bearing L1210 leukemia.

Animals↗
PubMed1978

Probenecid inhibition of methotrexate-cerebrospinal fluid pharmacokinetics in dogs.

Cerebrospinal fluid (CSF) and plasma concentrations of methotrexate (MTX) were followed in dogs for 72 hours after intracisternal injection of MTX with and without probenecid pretreatment. CSF levels declined as a biexponential function of time. Probenecid pretreatment of the animals prolonged the second phase half-disappearance time of MTX from 5.20 +/- 0.89 to 7.086 +/- 0.23 hours (mean +/- SD). The peak mean plasma concentration of MTX was lower in the presence of probenecid. Also, the rate of decline of plasma MTX concentrations was slower after treatment with probenecid, with mean half-disappearance times of 7.60 +/- 0.77 and 11.32 +/- 1.08 hours. These CSF and plasma data support the proposal that probenecid inhibits the transfer of MTX from CSF to blood.

Animals↗
PubMed1981

Clinical application of the probenecid test for measurement of monoamine turnover in the CNS.

The probenecid-induced accumulation of the acidic metabolites of dopamine and serotonin is widely used to estimate the CNS turnover of these amines in human subjects. The theoretical basis of the probenecid test is discussed, including the assumptions on which the test is based, and the limitations of the procedure. Suggestions are offered on appropriate methods for analyzing test data. Available evidence suggests that maximal inhibition of the efflux of the acidic metabolites of dopamine and serotonin from the CSF is not achieved with probenecid doses up to 100 mg/kg. Therefore, before a comparison can be made between the accumulation of CSF metabolites from different groups of subjects, a correction for CSF probenecid concentrations is necessary. Moreover, in addition to the measurement of dopamine and serotonin turnover, the probenecid test can be extended to include comparisons of CNS turnover of other monoamines including octopamine, p-tyramine, and tryptamine.

Brain↗
PubMed1983

Cerebrospinal fluid probenecid studies: a reinterpretation.

Probenecid is used to block the transport of acid monoamine metabolites from cerebrospinal fluid (CSF), on the assumption that the resultant rise in CSF concentrations of the metabolites will reflect presynaptic "turnover" of the parent monoamine. However, CSF levels of probenecid correlate with CSF levels of the metabolite, suggesting that the blockade is incomplete at the probenecid levels obtained in human studies. This article reviews the literature on CSF probenecid-metabolite correlations and presents data demonstrating variations in the correlations across diagnostic groups. These cross-diagnostic variations may be due to group differences in membrane transport characteristics and and confound attempts to "correct for" CSF probenecid concentrations in studies of monoamine turnover.

Biological Transport↗
PubMed1976

The effect of probenecid on the free and conjugaed 3-methoxy-4-hydroxyphenylglycol (MHPG) in lumbar cerebrospinal fluid.

Free and conjugated lumbar cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured before and after probenecid treatment in 12 schizophrenic patients by a gas liquid chromatography-mass fragmentographic procedure. Neither the free nor conjugated MHPG was appreciably altered by probenecid. Total MHPG was statistically increased by probenecid but not to the point that the probenecid test would be clinically useful for estimating norepinephrine turnover from probenecid-induced changes in MHPG concentrations.

3-Methoxy-4-hydroxyphenylethanol↗
PubMed1993

Probenecid-resistant J774 cell expression of enhanced organic anion transport by a mechanism distinct from multidrug resistance.

Macrophages possess organic anion transporters that carry membrane-impermeant fluorescent dyes, such as lucifer yellow (LY) and carboxy-fluorescein, from the cytoplasm into endosomes and out of the cells. Probenecid, an organic anion transport inhibitor, blocks these processes. Prolonged incubation of J774 cells in medium containing 2.5 mM probenecid eventually kills most of these cells. To identify J774 variants that express increased organic anion transport activity, we selected probenecid-resistant (PBR) J774 cells by growing them in medium containing increasing concentrations of probenecid. When PBR and unselected J774 cells were loaded with LY by ATP4- permeabilization, the amount of LY accumulated by the PBR cells was about half that in the unselected cells. This difference was abolished by adding 10 mM probenecid to the medium in which the cells were loaded, suggesting that the diminished LY accumulation in PBR cells was due to enhanced LY secretion and that the PBR cells expressed increased organic anion transport activity. Direct comparison of LY efflux from J774 and PBR J774 cells showed a faster initial rate of secretion of LY from PBR J774 cells than from unselected J774 cells. To determine whether LY efflux is mediated by P-glycoprotein, we compared LY efflux in unselected J774 cells, PBR J774 cells, and multidrug-resistant J774 cells (J7.C1). LY efflux from J7.C1 cells was not sensitive to verapamil, which inhibits multidrug-resistance transporters, and reverses the multidrug-resistant phenotype of J7.C1 cells. The rates of LY efflux from unselected J774 and J7.C1 cells were virtually identical.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

In vivo evidence for carrier-mediated efflux transport of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine across the blood-brain barrier via a probenecid-sensitive transport system.

By analyzing the amount of ligand remaining in the brain after microinjection into the brain cortex, the apparent efflux rate constants (Keff) of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (DDI) across the blood-brain barrier at low concentrations were determined to be 0.0317 +/- 0.0068 min(-1) and 0.0253 +/- 0.0037 min(-1), respectively. At higher concentrations, efflux exhibited saturation. The concentration of unlabeled DDI to inhibit 50% of the saturable efflux of [3H]DDI was found to be 11.3 +/- 5.7 microM, assuming that DDI diffused into the same volume of brain as that of trypan blue after intracerebral administration. The efflux rate of [3H]AZT from the brain was significantly inhibited by DDI, probenecid, p-aminohippuric acid, benzylpenicillin and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, but not by thymidine. Moreover, the efflux rate of [3H]DDI was significantly inhibited by AZT and probenecid, but not by deoxyinosine and inosine. After intracerebroventricular injection, the apparent efflux clearances of [3H]AZT and [3H]DDI from the cerebrospinal fluid were significantly inhibited by the coadministration of probenecid. However, intracerebroventricularly administered probenecid had no effect on the efflux of [3H]AZT and [3H]DDI from the brain after intracerebral microinjection, which suggested that the efflux transport system of the blood-cerebrospinal fluid barrier is not responsible for the elimination of AZT and DDI from the cerebral cortex. These results provide kinetic evidence that AZT and DDI are transported from brain into circulating blood across the blood-brain barrier via a probenecid-sensitive carrier-mediated efflux transport system.

Animals↗
PubMed1998

No effect of probenecid on the renal excretion mechanism of a new carbapenem, DA-1131, in dogs.

The effect of probenecid, an anion transport inhibitor, on the renal excretion mechanism of a new anionic carbapenem, DA-1131, was investigated after 1-min intravenous infusion of DA-1131, 10 mg/kg, with or without probenecid, 50 mg/kg, to dogs. The renal clearance (CL(R)) of DA-1131 in dogs without probenecid (3.18+/-0.247 ml/min/kg) was considerably smaller than the reported creatinine clearance (CL(CR)) in dogs, 6.13 ml/min/kg, indicating that renal tubular reabsorption of the drug was observed in dogs. However, the CLR of DA-1131 was not significantly different (3.18+/-0.247 versus 3.29+/-0.698 ml/min/kg) by treatment with probenecid indicating that the tubular reabsorption of DA-1131 was not inhibited by probenecid.

Absorption↗
PubMed1978

Probenecid-induced norepinephrine elevations in plasma and CSF.

Probenecid administered in divided oral doses totaling 100 mg/kg increased levels of norepinephrine (NE) in plasma and cerebrospinal fluid (CSF). This technique is commonly used to measure the rate of accumulation of acidic metabolites of certain brain neurotransmitter biogenic amines in CSF after blockade of their transport into blood. Since levels of 3-methoxy-4-hydroxy-phenylethyleneglycol, a neutral metabolite of NE, are also elevated after high oral doses of probenecid, the increases of CSF and plasma NE levels may be directly related to probenecid-induced release of this amine from noradrenergic neurons. In patients who experienced nausea or vomiting there were lower levels of probenecid in CSF, probably secondary to diminished absorption of the medication. These patients also had lower levels of NE in plasma than did patients who remained asymptomatic.

Adolescent↗
PubMedDate not supplied

Physiologically based pharmacokinetic model for the renal clearance of iodopyracet and the interaction with probenecid in the dog.

Plasma kinetics and renal excretion of iodopyracet (3.0 g, administered i.v.) with and without concomitant administration of probenecid were studied in the beagle dog. Pharmacokinetic analysis revealed that tubular secretion is the predominant route of excretion, and that secretion is inhibited by probenecid. A physiologically based kidney model is proposed comprising all the functional characteristics of the kidney that determine the excretion of iodopyracet, i.e. renal plasma flow, urine flow, protein binding, glomerular filtration, tubular secretion, and tubular accumulation. The model enabled an accurate description and analysis of the measured plasma levels and renal excretion rates. Renal clearance of iodopyracet is characterized by supply-limited elimination at low plasma concentrations and capacity-limited elimination at high plasma levels. The interaction with probenecid could be adequately described with the model by competitive inhibition of the carrier-mediated uptake of iodopyracet into the tubular cells. Model calculations showed that in the control experiments tubular secretion was accompanied by a pronounced accumulation of iodopyracet within the cells, which was clearly diminished in the presence of probenecid.

Animals↗
PubMed1993

Inhibition of acetaminophen and lorazepam glucuronidation in vitro by probenecid.

The effect of probenecid on glucuronidation of acetaminophen and lorazepam in hepatic microsomes from various species was studied to see if in vitro results were consistent with previous in vivo observations. Mouse, rat, and human microsomes were incubated with acetaminophen and probenecid while monkey microsomes were incubated with lorazepam and probenecid. Glucuronidation rates in all species varied with substrate, protein, and detergent concentrations. Mice exhibited faster rates of glucuronidation than rats or humans. All species showed inhibition of glucuronidation of acetaminophen or lorazepam when probenecid was added. Analysis suggested competitive inhibition. Thus, in vitro studies support in vivo results and confirm that the inhibition takes place at the hepatic level.

Acetaminophen↗
PubMed2003

Probenecid-induced changes in the clearance of pranoprofen enantiomers.

Probenecid is known to inhibit the elimination of several acidic drugs. Its influence on the pharmacokinetics of pranoprofen was investigated in rabbit after a single intravenous injection of racemic mixture (5 mg/kg). Levels of (-)-(R)- and (+)-(S)-pranoprofen and their glucuronide (after hydrolysis with sodium hydroxide) were determined in plasma, urine, and several tissues. The plasma concentration of the (+)-(S)-isomer was higher than that of the (-)-(R)-form. Oral coadministered probenecid (100 mg/kg) resulted in an increased plasma concentration of both enantiomers. Probenecid reduced the apparent total clearance and excretion of pranoprofen enantiomers in urine. It had a slight effect on the tissue distribution of pranoprofen at the dose used, but significantly reduced the formation of glucuronide for both enantiomers to the same extent in kidney microsomes. The differences caused by probenecid were significant with respect to its ability to inhibit glucuronidation in the kidney and subsequent excretion into urine, but enantioselective effects were negligible.

Animals↗
PubMed1977

Influence of probenecid and spironolactone on furosemide kinetics and dynamics in man.

The pharmacokinetics and pharmacodynamics following administration of furosemide (40 mg intravenously) have been studied before and after treatment with probenecid (0.5 gm orally every 6 hr for 3 days) and spironolactone (200-mg initial oral dose followed by 50 mg every 6 hr for 3 days) in 6 normal male subjects. Urine losses during each study period were replaced with saline-dextrose-KCl intravenously. The study was performed with the use of a Latin-square design. Probenecid pretreatment induced significant reductions in renal clearance of furosemide by 78%, the extrarenal clearance by 56%, and the volume of distribution by 52%. As a consequence, furosemide half-life was increased by 54%. Probenecid significantly reduced the rate of sodium excretion at all plasma concentrations of furosemide, but the ratio between urinary furosemide concentration and urinary sodium concentration was not altered. Since the proportion of furosemide excreted unchanged in the urine was not markedly changed, total diuretic response was not influenced by probenecid. There was no evidence of any pharmacokinetic interaction between spironolactone and furosemide. The relationship of furosemide kinetics to dynamics observed in these studies confirms that, in man, the diuretic response is determined by drug that reaches the renal tubule rather than the drug level in plasma.

Adult↗