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PubMed1987

Effect of probenecid on rat brain phenolsulfotransferase activity using dopamine as substrate.

Dopamine sulfate (DAS) is formed by the action of phenolsulfotransferase (PST) on dopamine (DA). Since probenecid is often used to investigate the transport of monoamine acidic metabolites such as DAS from the brain, we investigated the effect of probenecid on rat brain PST activity utilizing DA as substrate. In the presence of 30 or 90 microM DA, probenecid had either no effect or a dose-related inhibitory effect on PST activity. PST activity increased at low probenecid concentrations, but decreased at high probenecid concentrations when 360 microM DA was utilized. Several conditions were found where PST activity was not affected by probenecid.

Animals↗
PubMed2001

Effect of probenecid on the kinetics of a single oral 400mg dose of moxifloxacin in healthy male volunteers.

OBJECTIVE: To investigate the effect of oral probenecid on the pharmacokinetics of oral moxifloxacin in healthy adult male volunteers. DESIGN AND SETTING: This was a nonblinded, randomised, 2-way crossover study. PATIENTS AND PARTICIPANTS: 12 male Caucasian volunteers (mean age 33.7 years) participated in the study. METHODS: A single oral dose of moxifloxacin 400mg was administered after an overnight fast with or without a 2-day course of probenecid 500mg twice daily starting at 1 hour before the moxifloxacin dose. There was a washout phase of at least 1 week between the 2 treatments. Samples of plasma and urine were taken according to predefined sampling schedules and the concentrations of moxifloxacin were determined with a validated high performance liquid chromatography assay with fluorescence detection. Noncompartmental pharmacokinetic data were calculated. RESULTS: Pharmacokinetic results with and without probenecid were virtually identical except for a slight delay in absorption with probenecid, indicated by a very slightly increased time to maximum concentration and a decreased maximum concentration (approximately 10%), which was not clinically relevant. Probenecid had no significant influence on the renal elimination of moxifloxacin, suggesting urinary excretion by glomerular filtration and partial tubular reabsorption. Safety and tolerability were good, with no clinically relevant drug-related adverse events or changes in laboratory parameters. CONCLUSION: Dosage adjustments for moxifloxacin are not necessary when it is administered together with probenecid.

Administration, Oral↗
PubMed1999

The role of probenecid-sensitive organic acid transport in the pharmacokinetics of N-methyl-D-aspartate receptor antagonists acting at the glycine(B)-site: microdialysis and maximum electroshock seizures studies.

The purpose of the present study was to determine whether the probenecid-sensitive organic acid transporter is responsible for the short duration of action of a new group of N-methyl-D-aspartate receptor glycine(B)-site antagonists, MRZ 2/570, 2/571, and 2/576. A prolongation of their anticonvulsant activity from 60 to 180 to 240 min, was found in mice after pretreatment with probenecid (200 mg/kg i.p.). Microdialysis studies in rats showed that this is likely due to a change in central nervous system concentrations of these drugs because cotreatment with probenecid caused an increase in the brain extracellular fluid half-life (0.5- to 4-fold) and the brain area under the curve (1.8- to 3.6-fold). In serum the half-life of MRZ 2/576 (30 mg/kg) was also increased by coadministration of probenecid from 15.6 +/- 1.3 to 40.6 +/- 6.0 min. At steady state (MRZ 2/576, 20 mg/kg/h i.v.), brain extracellular fluid concentration was elevated 2.5-fold by concomitant administration of probenecid. These results clearly show that these glycine(B)-site antagonists are rapidly cleared from the systemic circulation and the central nervous system by the probenecid-sensitive organic acid transport system. Moreover, the present data show that MRZ 2/570, 2/571, and 2/576 reach the brain in concentrations (1.34-2.32 microM) above the range of their in vitro potencies at the glycine site of the N-methyl-D-aspartate receptor (0.1-1.0 microM).

Animals↗
PubMed1985

Probenecid impairment of acetaminophen and lorazepam clearance: direct inhibition of ether glucuronide formation.

Eleven subjects received acetaminophen (650 mg i.v.) on two occasions in random sequence, with and without concurrent administration of probenecid (500 mg) every 6 hr. Nine subjects similarly received lorazepam (2 mg. i.v.) with and without concurrent probenecid. Acetaminophen half-life was prolonged during probenecid treatment (mean +/- S.E., 4.30 +/- 0.23 vs. 2.51 +/- 0.16 hr; P less than .001) due to markedly decreased clearance (178 +/- 13 vs. 329 +/- 24 ml/min; P less than .001) with no change in volume of distribution (65 +/- 4 vs. 69 +/- 3 l; NS). Urinary excretion of acetaminophen glucuronide during 24 hr was decreased (84 +/- 9 vs. 260 +/- 21 mg of acetaminophen as glucuronide; P less than .001) and acetaminophen sulfate excretion was increased (323 +/- 25 vs. 217 +/- 17 mg of acetaminophen as sulfate; P less than .005) during concurrent probenecid treatment. However, the sum of the two conjugated metabolites was not significantly different (407 +/- 28 vs. 476 +/- 20 mg of acetaminophen as glucuronide plus sulfate excreted per 24 hr; NS). Lorazepam half-life was also prolonged during probenecid treatment (33.0 +/- 3.9 vs. 14.3 +/- 1.08 hr; P less than .001) due to decreased clearance (44.7 +/- 5.4 vs. 80.3 +/- 13.2 ml/min; P less than .001) with no change in volume of distribution (111 +/- 5 vs. 111 +/- 7 l; NS). Formation of the ether glucuronides of acetaminophen and lorazepam is impaired markedly by therapeutic doses of probenecid. Sulfate conjugation is not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1984

Probenecid inhibition of methotrexate cytotoxicity in mouse L1210 leukemia cells.

The effect of probenecid on methotrexate cytotoxicity has been measured using mouse L1210 leukemia cells in vitro. Cytotoxic effects were measured using a soft agar cloning technique. Cell exposure to varying concentrations of methotrexate at fixed concentrations of probenecid resulted in increased cell survival when compared with exposure to methotrexate alone. Cell exposure to a fixed concentration of methotrexate and varying concentrations of probenecid showed this effect to be dependent on the concentration of probenecid. Intracellular methotrexate concentrations were unchanged by the presence of probenecid. However, there was an effect of probenecid on progression of cells through the cell cycle which would tend to decrease the number of cells susceptible to the cytotoxic effects of methotrexate.

Animals↗
PubMed1995

Probenecid inhibits the renal clearance of frusemide and its acyl glucuronide.

The effect of oral probenecid (1 g) on the pharmacokinetics of frusemide (80 mg p.o.) and its acyl glucuronide was studied in nine healthy subjects. Probenecid significantly increased the t1/2,z of frusemide from 2.01 +/- 0.68 to 3.40 +/- 1.48 h (P = 0.0015) and significantly decreased oral clearance from 164 +/- 67.0 to 58.3 +/- 28.1 ml min-1 (P = 0.0001). No effect of probenecid on the plasma protein binding of frusemide was detected. Probenecid significantly increased the tmax of the metabolite frusemide acyl glucuronide from 1.4 to 2.6 h, but had no effect on the tlag, Cmax, t1/2,z and plasma protein binding. The urinary recoveries of unchanged frusemide (39.2 +/- 10.2 vs 34.4 +/- 8.6%, P = 0.28) and its acyl glucuronide (12.1 +/- 2.7 vs 11.8 +/- 3.7%, P > 0.8) were not altered by probenecid. However, probenecid decreased the renal clearance of both frusemide (128 +/- 49 vs 44.0 +/- 18.6 ml min-1, P = 0.0002) and the acyl glucuronide (552 +/- 298 vs 158 +/- 94.0 ml min-1, P < 0.0001). The non-renal clearance of frusemide (36.7 +/- 21.0 vs 15.2 +/- 13.4 ml min-1, P = 0.0068) was also decreased. The clinical relevance of the study relates to the possible conjugation of frusemide in the kidney and the role of the conjugate in the pharmacodynamic effect.

Adult↗
PubMed1998

Probenecid alters topotecan systemic and renal disposition by inhibiting renal tubular secretion.

Topotecan is primarily eliminated by the kidneys, with 60 to 70% of the dose recovered as topotecan total in the urine. To elucidate the mechanisms of topotecan renal clearance, we evaluated the effect of probenecid on topotecan renal and systemic disposition in mice. Topotecan lactone or hydroxy acid (1.25 mg/kg i.v.) was administered alone or in combination with probenecid (600 or 1,200 mg/kg) given by oral gavage 30 min before and 3 hr after topotecan. Serial blood samples (three mice per time point) and urine samples (five mice per treatment arm) were collected during a 6-hr period. Compared with topotecan alone, coadministration of topotecan lactone or hydroxy acid with probenecid (600 mg/kg) decreased topotecan lactone, total, and hydroxy acid systemic clearance, and total renal clearance. The predominant effect of probenecid was to increase hydroxy acid area under the plasma concentration time curve after administration of topotecan lactone (238.8 vs. 109.9 ng.hr/ml alone, P < .05), or hydroxy acid (1297.2 vs. 355.0 ng.hr/ml alone, P < .05). By inhibiting renal tubular secretion, probenecid decreased renal and systemic clearance which led to an increase in topotecan systemic exposure. These data suggest that probenecid primarily inhibited secretion of the anionic hydroxy acid form, and by direct or indirect mechanisms increased topotecan lactone systemic exposure. Topotecan elimination through renal tubular secretion may have clinical relevance for the use of topotecan in patients with altered renal function.

Animals↗
PubMed1977

Effects of probenecid on furosemide kinetics and natriuresis in man.

Furosemide kinetics were studied in 4 normal subjects after single intravenous injections (1 mg/kg). One experiment was done after pretreatment with probenecid. The apparent volume of furosemide distribution was unchanged after probenecid (10.9 L). The mean plasma clearance fell from 155 to 85 ml/min and the mean plasma t1/2 rose from 36 to 61 min. Renal clearance of furosemide fell below 50% of control after probenecid, but the kidney remained the main route of its excretion (75% of the dose appeared in the urine). In another experiment in 4 subjects an infusion of furosemide was sustained following a loading dose to maintain a constant plasma level. After a control period, probenecid was given orally. This resulted in a decrease in renal excretion of furosemide with a simultaneous rise in its plasma concentration. Despite the rising plasma furosemide concentration, however, there was a diminution in both urine flow and the excreted fraction of filtered sodium, which suggested some reduction of diuretic action. In doses commonly used, probenecid reduces renal elimination of furosemide in man with only a mild impairment of its diuretic activity. This suggests that furosemide is eliminated predominantly by way of proximal tubular secretion and that tubular rather than plasma concentration is the main determinant of its diuretic effect.

Drug Interactions↗
PubMed1978

Increase in diuretic effect of chlorothiazide by probenecid.

Thiazide diuretics reach their presumed intraluminal site of action by active transport at the organic acid secretory site of the proximal tubule. Probenecid competes for this transport and might therefore affect the diuresis induced by thiazide at that site. Doses of 500 mg and 1 gm of chlorothiazide (CTZ) intravenously to 5 volunteers with probenecid pretreatment increased 8-hr rates of excretion of sodium and urine over that without probenecid. Eight-hour excretion of sodium after administering 500 mg of CTZ was 147 +/- 7.5 mEq and 257.9 +/- 16.4 mEq after CTZ with probenecid (p less than 0.0005). The volume of urine after CTZ was 728 +/- 37 ml and 1,886 +/- 301 ml after CTZ with probenecid (p less than 0.001). This increase was associated with prolongation of CTZ diuresis rather than increase in intensity. These results are consistent with CTZ reaching its site of action from the peritubular side or that prolonged exposure of the lumen to lesser amounts of filtered CTZ causes a greater overall effect.

Adult↗
PubMed1990

The inhibitory effect of probenecid on renal excretion of famotidine in young, healthy volunteers.

Effects of coadministration of probenecid on pharmacokinetic behaviors of famotidine, an H2-receptor antagonist, after oral administration, were studied in eight young, healthy volunteers. They received an oral 20 mg dose of famotidine with and without coadministration of oral 1500 mg doses of probenecid. The mean area under the serum famotidine concentration-time curve up to 10 hours was increased by coadministration of probenecid from 424 +/- 19 (SEM) to 768 +/- 39 ng.hr/ml. The mean urinary excretion rate of unchanged famotidine, the mean amount of unchanged famotidine excreted in urine up to 24 hours and mean renal clearance were decreased by coadministration of probenecid. The mean tubular secretion clearance of famotidine was decreased from 196.2 +/- 21.4 to 22.0 +/- 4.2 ml/min. These data suggest that probenecid, which is a classical inhibitor of renal tubular secretion of organic anions, inhibits the renal tubular secretion of famotidine, which exists partly in a cationic form under physiological pH conditions.

Adult↗
PubMed1990

Lack of probenecid effect on nonrenal excretion of ceftriaxone in anephric patients.

Probenecid has been shown to decrease renal and biliary excretion of organic acids. In a randomized crossover study, the effect of coadministered probenecid on nonrenal excretion of ceftriaxone was studied in six functionally anephric patients in whom ceftriaxone is eliminated exclusively by nonrenal or presumably by biliary excretion. Each patient received 0.5 g IV ceftriaxone without and with probenecid (0.5 g at 10 and 2 hours prior to ceftriaxone and 0.5 g q12h X 3 doses post ceftriaxone). Serial blood samples were collected over 48 hours and plasma analyzed for ceftriaxone by high performance liquid chromatography (HPLC). Pharmacokinetic analysis was based on a model-independent approach. Probenecid did not significantly affect the disposition of ceftriaxone in this study, thus suggesting that nonrenal excretion of ceftriaxone is not inhibited by probenecid.

Adult↗
PubMed1992

The effects of probenecid on the excretion kinetics of stanozolol, an anabolic steroid, in rats.

The pharmacokinetic behaviour and the mechanism of renal excretion of stanozolol (STZ), as affected by co-treatment with probenecid, were studied in male Sprague-Dawley rats. Pharmacokinetic parameters following intravenous (i.v.) administration of STZ (20 mg kg-1 body wt.) were measured in both STZ-treated (control) and STZ plus probenecid-treated (treatment) groups. In order to assess the renal clearance of STZ, bolus doses of STZ and inulin (40 mg kg-1 body wt.) were injected i.v. either in the presence or absence of probenecid (40 mg kg-1 body wt.). The blood and urine concentrations of STZ were determined by capillary gas chromatography-mass spectrometry (GC-MS). In the probenecid treatment group, the area under the plasma disappearance and urinary excretion curves (AUC) of STZ were significantly decreased (P < 0.01) and the volume of distribution (Vd) and total clearance (CLt) were significantly increased statistically (P < 0.05 and P < 0.01, respectively). No remarkable differences in the urine flow rate, urine pH values, glomerular filtration rate (GFR) or renal clearance were observed in the treatment group. However, the clearance ratio in the treatment group was significantly increased from 11.72 to 17.27. From these results, it is suggested that the significant decrease of AUC, i.e. increase of disappearance of STZ in plasma by co-administration with probenecid, is due to the increase of the clearance ratio.

Animals↗
PubMed1996

The effect of induced fever on the biokinetics of norfloxacin and its interaction with probenecid in goats.

The kinetic profiles of norfloxacin were evaluated in afebrile, febrile and probenecid pre-treated (70 mg/kg orally) febrile goats after a single intravenous (i.v.) dose (5 mg/kg). Fever was induced and maintained for 12 h by injecting Escherichia coli endotoxin (0.2 microgram/kg, i.v.) and repeating it in half the dose (0.1 microgram/kg) 5 h later. The plasma pharmacokinetic values for norfloxacin were best represented using a two-compartment open model. The peak norfloxacin plasma level of 90.52 +/- 3.18 micrograms/ml attained in the probenecid pre-treated febrile goats was higher than that in the febrile (75.46 +/- 0.72 micrograms/ml) or afebrile goats (62.25 +/- 1.23 micrograms/ml). ClB and Kel values were significantly (p < 0.01) decreased in febrile compared with afebrile goats. These values were further reduced in febrile goats after probenecid pre-treatment. However, t1/2 beta was not affected by the fever-probenecid interaction. Norfloxacin may be used as an infusion with probenecid in caprine diseases where very high plasma levels are required to combat resistant organisms such as Bacteroides.

Analysis of Variance↗
PubMed1983

The effects of probenecid on cyclic adenosine 3',5'-monophosphate levels in cerebrospinal fluid and on brain phosphodiesterase activity in the rat.

In rats, probenecid exhibits a dose-dependent increase in the concentration of cyclic adenosine 3',5'-monophosphate (cAMP) in cisternal cerebrospinal fluid (CSF). Maximal accumulation is reached 2 h after IP administration at a dosage of 150 mg/kg body weight. Serum levels of cAMP are unchanged after 200 mg/kg probenecid. In vitro investigations show an inhibitory effect of probenecid on the uptake of cAMP into the isolated choroid plexus of the rabbit. A non-competitive inhibition of probenecid on a high affinity fraction of cyclic nucleotide phosphodiesterase from rat brain homogenates is demonstrated with an inhibitor constant of 3.4 X 10(-3M. The results appear to validate the "probenecid test" for cAMP in clinical diagnostics.

Animals↗
PubMed1987

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

Plasma kinetics and renal excretion of intravenous phenolsulfonphthalein (PSP, 1.0 g), with and without concomitant administration of probenecid or salicyluric acid (SUA), 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 and SUA. A physiologically based kidney model was developed that incorporates the functional characteristics of the kidney that determine the excretion of PSP, i.e., renal plasma flow, urine flow, nonlinear 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. The interaction with probenecid and SUA could be adequately described with the model by inhibition of the carrier-mediated uptake of PSP into the proximal tubular cells. However, both compounds clearly differed in their inhibitory action. Whereas probenecid showed simple competitive inhibition, for SUA a considerably more complex interaction (two-site competitive system) had to be taken into consideration. Especially in the interaction experiments, only satisfactory fits to the model were obtained when secretion was assumed to be dependent on unbound PSP concentrations. Model calculations showed that in the control experiments tubular secretion was accompanied by a pronounced accumulation of PSP within the proximal tubular cells, which was clearly diminished in presence of probenecid or SUA. The predicted accumulation ratios were in good agreement with previous studies.

Animals↗
PubMed1978

Kinetics studies on the renal transport of probenecid in vitro.

1. The kinetic parameters of renal transport of probenecid have been assessed by studying the uptake of the drug in rabbit kidney tubules incubated in an electrolyte medium under various conditions. 2. The added compounds inhibited the uptake of probenecid both by kidney cortical slices and separated renal tubule preparations in the following order: p-aminohippurate less than phenol red less than bromophenol blue less than bromocresol green. A reversible competitive inhibitory effect of these organic anions on the renal accumulation of the drug was observed. 3. The Km for renal uptake of probenecid in separated tubules (0.04 mM) and the KI values calculated in this system for p-aminohippurate (0.5 mM), phenol red (0.09 mM), bromophenol blue (0.02 mM) and bromocresol green (0.015 mM) were found to be in good agreement with the corresponding KI value of probenecid and Km values of these compounds previously observed in various kidney tissue preparations. 4. On the basis of above mentioned findings, it is concluded that probenecid, p-aminohippurate and various phenolsulphonphthalein dyes are transported by the common renal organic anion transport system.

Animals↗
PubMed1977

Dihydroxyphenylacetic acid conjugate: natural occurrence and demonstration of probenecid-induced accumulation in rat striatum, olfactory tubercles and frontal cortex.

Methods for the synthesis of 14C-dihydroxyphenylacetic acid (DOPAC) conjugate and for the fluorometric determination of both free and conjugated DOPAC in the same tissue sample are described. Both free and conjugated DOPAC were demonstrated to occur endogenously in the rat corpus striatum, olfactoy tubercles and frontal cortical area, and the ratio of conjugated DOPAC to free DOPAC was 2-3 times greater in the olfactory tubercles and frontal cortical area than in the striatum. Probenecid administration (200 mg/kg, i.p., 4 and 2h before sacrificing) significantly increased the levels of DOPAC conjugate in all 3 brain areas studied. The levels of free DOPAC were also increased in the olfactory tubercles and frontal cortex by the probenecid treatment, but this increase was much less than that seen for DOPAC conjugate in these regions. Free DOPAC levels in the striatum were unaffected by the probenecid treatment. In all 3 brain areas studied, therefore, probenecid treatment resulted in a significant accumulation of conjugated DOPAC relative to free DOPAC. The magnitude of this effect varied, and was most marked in the frontal cortex. These results suggest that, in order for DOPAC to be transported from the central nervous system via a probenecid-sensitive transport system, it must first be conjugated. Additionally, it appears that the rates of synthesis, metabolism, and transport for both free and conjugated DOPAC may vary greatly among different dopamine-containing brain regions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Interaction between probenecid and two lipid-soluble barbiturates in the rat.

The effect of pretreatment with probenecid (200 mg/kg, i.p.) on the sensitivity of the central nervous system (CNS) to thiopental and hexobarbital was investigated with an EEG-threshold method. The threshold dose was significantly decreased by pretreatment with probenecid for thiopental but not for hexobarbital. This was due to an increased penetration of thiopental into the CNS, but for hexobarbital an increase in penetration could also be demonstrated by analysis of brain and serum concentrations after infusion of an equal dose of barbiturate. The concentrations in brain at the EEG-threshold were not influenced by pretreatment with probenecid for either of these barbiturates, which shows that there was no synergism between these barbiturates and probenecid due to the depressant effect of probenecid on the CNS.

Animals↗