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PubMed1999

Quinolinic acid is extruded from the brain by a probenecid-sensitive carrier system: a quantitative analysis.

Although the neurotoxic tryptophan-kynurenine pathway metabolite quinolinic acid originates in brain by both local de novo synthesis and entry from blood, its concentrations in brain parenchyma, extracellular fluid, and CSF are normally below blood values. In the present study, an intraperitoneal injection of probenecid (400 mg/kg), an established inhibitor of acid metabolite transport in brain, into gerbils, increased quinolinic acid concentrations in striatal homogenates, CSF, serum, and homogenates of kidney and liver. Direct administration of probenecid (10 mM) into the brain compartment via an in vivo microdialysis probe implanted into the striatum also caused a progressive elevation in both quinolinic acid and homovanillic acid concentrations in the extracellular fluid compartment but was without effect on serum quinolinic acid levels. A model of microdialysis transport showed that the elevations in extracellular fluid quinolinic acid and homovanillic acid levels following intrastriatal application are consistent with probenecid block of a microvascular acid transport mechanism. We conclude that quinolinic acid in brain is maintained at concentrations below blood levels largely by active extrusion via a probenecid-sensitive carrier system.

Animals↗

PubMed2002

Pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin in goats given enrofloxacin alone and in combination with probenecid.

The pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin were investigated in goats given enrofloxacin alone or in combination with probenecid. Enrofloxacin was administered i.m. at a dosage of 5 mg x kg(-1) alone or in conjunction with probenecid (40 mg x kg(-1), i.v.). Blood samples were drawn from the jugular vein at predetermined time intervals after drug injection. Plasma was separated and analysed simultaneously for enrofloxacin and ciprofloxacin by reverse-phase high performance liquid chromatography. The plasma concentration-time data for both enrofloxacin and ciprofloxacin were best described by a one-compartment open pharmacokinetic model. The elimination half-life (t(1/2beta)), area under the plasma concentration-time curve (AUC), volume of distribution (V(d(area))), mean residence time (MRT) and total systemic clearance (Cl(B)) were 1.39 h, 7.82 microg x h x mL, 1.52 L x kg(-1), 2.37 h and 802.9 mL x h(-1) x kg(-1), respectively. Enrofloxacin was metabolized to ciprofloxacin in goats and the ratio between the AUCs of ciprofloxacin and enrofloxacin was 0.34. The t(1/2beta), AUC and MRT of ciprofloxacin were 1.82 h, 2.55 microg x h x mL and 3.59 h, respectively. Following combined administration of probenecid and enrofloxacin in goats, the sum of concentrations of enrofloxacin and ciprofloxacin levels > or = 0.1 microg x mL(-1) persisted in plasma up to 12 h.Co-administration of probenecid did not affect the t(1/2beta), AUC, V(d (area)) and Cl(B) of enrofloxacin, whereas the values of t(1/2beta) (3.85 h), AUC (6.29 microg x h x mL), MRT (7.34 h) and metabolite ratio (0.86) of ciprofloxacin were significantly increased. The sum of both enrofloxacin and ciprofloxacin levels was > or = 0.1 microg x mL(-1) and was maintained in plasma up to 8 h in goats after i.m. administration of enrofloxacin alone. These data indicate that a 12 h dosing regime may be appropriate for use in goats.

Animals↗

PubMed1985

Renal tubular secretion and reabsorption as factors in ochratoxicosis: effects of probenecid on nephrotoxicity.

Ochratoxin A (OA) is a food-borne fungal metabolite capable of producing nephrotoxicity. Renal clearance of [3H]OA and the effects of probenecid on clearance were compared in sham-operated and partially nephrectomized (surgical removal of 70% of the total renal mass), impaired renal function rats. Sham-operated and partially nephrectomized rats cleared OA at 0.109 and 0.078 ml/min, respectively. These values were significantly lower than glomerular filtration rate (GFR) determined by inulin clearance, indicating net tubular reabsorption. Clearance of a single dose of OA in both sham-operated and partially nephrectomized rats pretreated with probenecid was significantly diminished and provided evidence for the involvement of secretory processes in the elimination of OA. Probenecid (administered before OA or simultaneously with OA) failed to prevent nephrotoxicity in rats exposed to five daily doses of mycotoxin. On the contrary, enhanced nephrotoxicity was exhibited. Decreases in urine osmolality, Na+ and K+ concentrations, and body weight were prominent and, interestingly, renal levels of parent OA were increased (over OA treatment alone) in the presence of probenecid. These data suggest that renal tubular secretion and reabsorption are important factors in modulating the nephrotoxicity of OA and may facilitate the residual persistence of this mycotoxin in the kidneys (via renal recycling). Renal metabolism may contribute to the detoxification of OA.

Absorption↗

PubMed1985

Immune hemolytic anemia associated with probenecid.

Upon hospital admission a patient was found to have severe anemia and a strongly positive direct antiglobulin test (DAT). The patient was taking probenecid periodically for gout. An antibody was detected in the patient's serum that only reacted with red blood cells (RBCs) when probenecid was added. Eluates from the patient's RBCs, with and without the presence of drug, were nonreactive. Upon the discontinuation of probenecid, the patient's hemoglobin level improved steadily. We believe this to be the first reported case of immune hemolytic anemia associated with probenecid.

ABO Blood-Group System↗

PubMedDate not supplied

Treatment of concomitant Neisseria gonorrhoeae and Chlamydia trachomatis infections in women: comparison of trimethoprim-sulfamethoxazole with ampicillin-probenecid.

Sixty-nine women with known or suspected uncomplicated gonorrhea were treated randomly either with a single dose of 3.5 g of ampicillin plus 1 g of probenecid or with four doses of trimethoprim-sulfamethoxazole (TMP-SMZ) in two double-strength tablets (160 mg of TMP plus 800 mg of SMZ) twice daily for two days. Overall, 56 (81%) of the women had gonococcal infections, 26 (38%) had chlamydial infections, and 23 (33%) had coexisting Chlamydia trachomatis and Neisseria gonorrhoeae infections. Among the women with genital or anal gonorrhea, two (9%) of 23 treated with TMP-SMZ and three (12%) of 25 treated with ampicillin and probenecid remained infected. TMP-SMZ cured four of four pharyngeal gonococcal infections. C. trachomatis was isolated at the first posttreatment visit significantly more often after treatment with ampicillin and probenecid (10 of 11 times) than after treatment with TMP-SMZ (1 of 10 times; P = 0.003). However, at the second follow-up visit, C. trachomatis was isolated from 30% of the women treated with TMP-SMZ. The area of ectopic columnar epithelium (ectopy) on the ectocervix and edema of this area were highly correlated with the presence of C. trachomatis, and persistence of C. trachomatis was associated with persistent edema of ectopy and with friability. TMP-SMZ is as effective as ampicillin-probenecid for the treatment of uncomplicated genital gonorrhea in women and may be more effective for the treatment of pharyngeal gonorrhea. The optimal dose and duration of TMP-SMZ therapy for C. trachomatis infection requires further study.

Adolescent↗

PubMed1975

Extraction of antibiotics from the circulation by liver and kidney: effect of probenecid.

An experimental canine model was designed to measure directly the uptake, storage, and excretion of antibiotics by the liver and kidney. At equilibirum the rate of uptake of penicillin G, cephalothin, and nafcillin by these organs was about 80% of the rate of intravenous infusion of each antibiotic. Penicillin G and cephalothin were extracted mainly by the kidneys, and nafcillin by the liver. Injection of probenecid virtually abolished the difference in concentration of antibiotic between afferent and efferent vessels of the liver and kidney after 30-45 min. Renal tubular secretion of penicillin G and cephalothin was suppressed, and their levels in renal tissue were increased. These findings militate against any primary limitation by probenecid of access of antibiotic to the renal parenchyma. A marked sustained increase (60%-70%) in the rate of portal flow followed injection of probenecid, and the concomitant percentage of nafcillin extracted by the liver declined significantly. Because of the circulatory changes, a specific effect of probenecid on acess of nafcillin to the liver could not be proved.

Animals↗

PubMed1983

The effects of irradiation and probenecid on cerebrospinal fluid transport of penicillin.

A hitherto unrecognized interaction between whole brain irradiation and probenecid on cerebrospinal fluid (CSF) transport of benzylpenicillin has been demonstrated in rabbits. Healthy adult rabbits received 10 Gy (1000 rad) to the whole brain as a single dose. At different time intervals after irradiation the animals were subjected to single intravenous injections of benzylpenicillin. Studies on benzylpenicillin concentrations in CSF showed increasing values one week after irradiation suggesting disturbance in blood-CSF barriers. Additionally, groups of rabbits were subjected to either irradiation, probenecid injections or both prior to antibiotic administration. All these treatments resulted in increased CSF concentration of benzylpenicillin relative to the concurrent serum levels. The increase of the CSF benzylpenicillin levels in the preirradiated animals was less pronounced in the animals treated with probenecid, compared to those who were irradiated only. The mode by which probenecid and irradiation interacts on the CSF kinetics of benzylpenicillin should be further evaluated.

Animals↗

PubMed1984

The effect of probenecid on serum amoxycillin concentrations up to 18 hours after a single 3 g oral dose of amoxycillin: possible implications for preventing endocarditis.

Serum concentrations of amoxycillin were significantly higher with probenecid than without probenecid for up to 18 h after administration of a single 3 g oral dose of amoxycillin. At 12 to 16 h after this dose the mean serum amoxycillin concentrations exceeded the expected minimum bactericidal concentrations of amoxycillin for viridans streptococci when probenecid was given together with amoxycillin. The concurrent oral administration of probenecid with amoxycillin is discussed for the prophylaxis of endocarditis in susceptible patients who require dental procedures under general anaesthesia.

Administration, Oral↗

PubMed1997

Comparison of dose doubling with probenecid for sustaining serum cefuroxime levels.

Serum cefuroxime concentrations were measured over a 12 h period in ten healthy adults following three iv dosing regimens: 750 mg cefuroxime, 1.5 g cefuroxime, and 750 mg cefuroxime with 1 g of probenecid given orally 3 h before the cefuroxime infusion. Probenecid prolonged the serum cefuroxime half-life by 63% (P < 0.05) with a significant increase in the mean time for which serum cefuroxime concentrations exceeded the MIC90 for common respiratory pathogens (2 mg/L) compared with either 750 mg cefuroxime (2.2 h, P < 0.05) or 1.5 g of cefuroxime (0.9 h, P < 0.05) without probenecid. The cost of the 750 mg cefuroxime dose plus probenecid is approximately half that of a 1.5 g cefuroxime dose.

Adolescent↗

PubMed1998

Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine, and probenecid in HIV-infected subjects.

The aim of this study was to determine whether oral ganciclovir interacted pharmacokinetically with zidovudine (AZT), didanosine (ddI), or probenecid. A multicenter, open-label, randomized, crossover pharmacokinetic study with four phases was undertaken at an outpatient private research center and at university research clinics. Twenty-six HIV-infected adults (23 men, 3 women) with cytomegalovirus (CMV) seropositivity and CD4+ T-lymphocyte count > or =100 cells/microl were studied. Patients had to be stable on antiretroviral therapy for at least 4 weeks. Patients with a history of opportunistic infection or gastrointestinal symptoms were excluded. Measurements included serial blood and urine samples during the dosing intervals at steady state. The steady-state pharmacokinetics of ganciclovir were determined after the participants had stabilized and were tolerating AZT or ddI therapy. When a 1000-mg dose of oral ganciclovir was taken every 8 hours, there was a significant mean increase in Cmax and dosing interval area under the serum concentration time curve over a dosing interval (AUC) for the two antiretroviral drugs: for AZT, 61.6% and 19.5%, respectively; for ddI when administered sequentially (2 hours before ganciclovir), 116.0% and 114.6%; and for ddI administered simultaneously with ganciclovir, 107.9% and 107.1%, respectively. There was no significant change in renal clearance for either antiretroviral drug, suggesting that the interaction did not occur through a renal mechanism. There was no significant change in mean ganciclovir Cmax and AUC(0-8) when coadministered with AZT. Mean increases in Cmax and AUC(0-8) of oral ganciclovir averaged 40.1% and 52.5%, respectively, when coadministered with probenecid, but decreased by 22.1% and 22.7%, respectively, when oral ganciclovir was administered 2 hours after ddI. There was no change in the mean ganciclovir Cmax or AUC(0-8) when administered simultaneously with ddI. The mean renal clearance of oral ganciclovir was not affected by AZT or ddI coadministration intake, but there was a mean decrease of 19% when coadministered with probenecid. We conclude the increased serum concentration and reduced renal clearance of ganciclovir suggests competition with probenecid for secretion at the renal tubule. The mechanism of the interaction of oral ganciclovir with either AZT or ddI remains to be determined. The magnitude of the effect of oral ganciclovir on ddI pharmacokinetics may result in an increase in ddI concentration-related toxicities. Similarly, the small but significant decrease in ganciclovir concentration with sequential combination ddl therapy may impair the efficacy of oral ganciclovir. For HIV-infected patients receiving ganciclovir and ddI, clinicians should recommend administering the two drugs simultaneously, and patients should be monitored closely for ddI-associated toxicities.

Administration, Oral↗

PubMed1981

Pharmacokinetics of cephradine given intravenously with and without probenecid.

1 In the light of questions raised by an earlier oral study (Welling, Dean, Selen, Kendall & Wise, 1979) the influence of probenecid on the pharmacokinetics of intravenously administered cephradine has been investigated. 2 Intravenous administration of cephradine resulted in a bi-exponential curve and the level of antibiotic after 15 min was significantly greater when subjects received probenecid than when they did not. The influence of probenecid on urinary excretion of cephradine was similar to that observed previously. 3 The increase in serum of cephradine due to probenecid could be accounted for by the decrease in the elimination rate of the antibiotic. These results are discussed in the light of other observations.

Adult↗

PubMed1984

The uricosuric action of azapropazone: dose-response and comparison with probenecid.

Azapropazone is an anti-inflammatory agent with reported uricosuric properties. The aim of the present study was to extend these observations, by examining the dose-response and to compare the uricosuric effect of azapropazone with that of probenecid. Patients were given varying doses of azapropazone from 900-2400 mg daily for 4-day periods at separated intervals. Plasma uric acid levels were measured before and at the end of each treatment period. Three other patients maintained on low purine diets were given a 4-day course of 1200 mg azapropazone daily followed at an interval by a 4-day period of probenecid 1 g daily. Plasma uric acid levels and 24 h urinary uric acid excretion were compared. The mean fall in plasma uric acid level after four days of 900 mg azapropazone daily was 31.4% (n = 9) compared with 33.9% (n = 12) on 1200 mg daily; 42.3% (n = 10) on 1800 mg daily; and 46% (n = 6) on 2400 mg daily, indicating a graded dosage response. In the three patients on low purine diets the falls in plasma uric acid levels on probenecid 1 g daily were 50.5%, 46% and 29% compared with 33.5%, 32% and 20% respectively on azapropazone 1200 mg daily. Similarly the total amount of uric acid excreted in the urine by each patient during the 4-day period on probenecid 1 g daily was 14.01; 13.03 and 8.97 mmol compared with 23.53, 10.9 and 7.69 mmol on azapropazone 1200 mg daily.(ABSTRACT TRUNCATED AT 250 WORDS)

Apazone↗

PubMed1991

No effect of probenecid on the renal and biliary clearances of digoxin in man.

1. The cardiac glycoside digoxin is subject to a number of pharmacokinetic interactions. This study concerns the influence of the anionic transport inhibitor probenecid on the steady-state kinetics of digoxin. 2. Six healthy young men were enrolled in the study. After an administration period of 6 days with digoxin only (0.5 to 1 mg p.o. day-1) or digoxin in combination with probenecid (2 g p.o. day-1; 8 days), digoxin was administered intravenously (0.7 oral dose) on day 7. Plasma and urine samples were taken over 48 h. The biliary clearance of digoxin was measured during day 8 by a duodenal perfusion technique. 3. Probenecid did not affect the plasma clearance (mean +/- s.d.: 255 +/- 80 vs 266 +/- 40 ml min-1), renal clearance (166 +/- 17 vs 155 +/- 10 ml min-1), biliary clearance (106 +/- 40 vs 111 +/- 50 ml min-1), elimination half-life (34.4 vs 35.2 h) or volume of distribution (538 +/- 241 vs 566 +/- 60 l) of digoxin. 4. Our results suggest that different systems exist in man for the renal and biliary secretion of probenecid and digoxin.

Administration, Oral↗

PubMed1994

Neither cimetidine nor probenecid affect the pharmacokinetics of tenoxicam in normal volunteers.

The effect of pretreatment with cimetidine (1 g day-1, 7 days) and of probenecid (1 g twice daily, 4 days) on the pharmacokinetics of tenoxicam (single oral dose, 20 mg) was studied in six healthy volunteers. Cmax was increased significantly when tenoxicam was given with probenecid (2.8 micrograms ml-1 alone, 3.5 micrograms ml-1 after probenecid; P < 0.005). No other pharmacokinetic parameters were altered significantly by either drug. It is concluded that neither cimetidine nor probenecid affects the pharmacokinetics of tenoxicam in a clinically important way.

Administration, Oral↗

PubMed1984

Pharmacokinetics of cefotaxime and probenecid in sheep with normal and reduced renal function.

The pharmacokinetics of cefotaxime and probenecid, given by intravenous injection, were determined in six Merino ewes which had been subjected to a 75% reduction in renal mass. These results were compared with results previously determined in sheep with normal renal function. In the sheep with reduced renal mass, the following significant changes in parameter values for cefotaxime were observed. The elimination rate constant (kel) decreased by 47%, the apparent volume of the central compartment (Vc) decreased by 59%, the steady state volume (Vss) decreased by 50%, and the total body clearance (ClB) decreased by 78%. The rate constant for distribution of drug into tissues (k12) increased 6.9 times, the rate constant for distribution out of tissues (k21) increased 3.7 times, and the area under the plasma concentration-time curve (AUC) increased by a factor of 4.9. The parameter values, determined in sheep with reduced renal mass, for probenecid plasma half-life, Vss and the rate constants k12, k21, and kel were not significantly different from the values obtained previously in sheep with normal renal mass. However, the rate constant for renal excretion of probenecid (ke), renal clearance (ClR), ClB and Vc decreased by 79, 90, 54 and 36%, respectively. The results indicate that reduced renal mass increased the plasma half-life for cefotaxime as well as increasing its diffusion into tissue. In the case of probenecid the overall distribution and elimination kinetics were not altered by reduced renal mass; however, the rate of urinary excretion of the drug was reduced.

Animals↗

PubMed1985

3,4-Dihydroxyphenylethylamine and 5-hydroxytryptamine metabolism in the rat: acidic metabolites in cisternal cerebrospinal fluid before and after giving probenecid.

3,4-Dihydroxyphenylethylamine (DA, dopamine) and 5-hydroxytryptamine (5-HT) turnover values were determined in freely moving male rats by measuring the rates of accumulation of the acidic metabolites of the above transmitters, i.e., 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in cisternal cerebrospinal fluid (CSF) samples after probenecid (200 mg/kg i.p.) administration. Determinations on samples before and after acid hydrolysis showed that the latter procedure was necessary for DA turnover determination. Thus whereas total (DOPAC + HVA) increased linearly with time after probenecid, free (DOPAC + HVA) did not. This was because the percentage of DOPAC + HVA in conjugated form increased with time. Determinations on a group of 28 rats during the dark (red light) period showed that cisternal amine metabolite concentrations before probenecid injection did not parallel turnover values. This was probably because individual differences in metabolite egress strongly affect the pre-probenecid values. The poor correlations between CSF tryptophan and 5-HT turnover suggested that differences of brain tryptophan concentration were not major determinants of differences of brain 5-HT metabolism within this group of normal rats. Considering that the rats were of similar weight and that the turnover values were all determined at approximately the same time of day, the three- to fourfold ranges of the turnover values are remarkable. The positive correlation between the DA and 5-HT turnovers of individual rats suggests the existence of common effects on DA and 5-HT turnover in normal rats.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1979

Clinicopharmacological evaluation of amoxicillin and probenecid against bacterial meningitis.

Forty-three infants and children with bacterial meningitis were treated intravenously with 200 mg of amoxicillin sodium per kg per day for 10 days. (Patients were initially treated with ampicillin and chloramphenicol until the bacterial etiology was defined.) Patients were randomly treated with amoxicillin only or with amoxicillin and four doses of probenecid (10 mg/kg per dose) orally every 6 h for 24 h before the lumbar puncture at day 10. Serum and cerebrospinal fluid (CSF) were obtained on days 1, 5, and 10 of therapy for antibiotic assay. The mean peak serum concentration of amoxicillin of 49.2 micrograms/ml was increased to 61.4 micrograms/ml in patients who received probenecid. The half-life in serum (1.5 h) and area under the curve with probenecid (112.5 micrograms/ml-h) were increased compared with those of amoxicillin alone (1.3 h and 82.2 micrograms/ml-h). The mean peak CSF concentrations on days 1 and 5 were similar, but day 1 concentrations remained between 2.0 micrograms/ml and 5.0 micrograms/ml throughout the 4 h after a dose, whereas the day 5 values decreased at the same decay rate as that in serum. All CSF concentrations were lower on day 10, but patients receiving probenecid had peak values occurring at 1 hr rather than at 0.5 h, and levels were significantly greater at 1 and 2 h after a dose. There were no deaths and patients responded well to treatment.

Amoxicillin↗

PubMed1989

Pharmacokinetics of intravenously administered cefmetazole and cefoxitin and effects of probenecid on cefmetazole elimination.

Sixteen healthy male volunteers participated in a randomized, balanced, three-way crossover study comparing the pharmacokinetics of cefmetazole, cefoxitin, and cefmetazole with probenecid pretreatment. Single 2-g doses of cefmetazole sodium and cefoxitin sodium were given intravenously as a 5-min infusion. Concentrations of cefmetazole and cefoxitin were determined by using a specific semiautomated high-performance liquid chromatographic method. Concentration-time profiles of cefmetazole and cefoxitin declined in a biexponential manner from peak levels. Compared with cefoxitin, cefmetazole had a significantly (P less than 0.05) higher mean (+/- standard error of the mean) peak concentration in serum (290 +/- 11 versus 244 +/- 10 micrograms/ml), a longer terminal disposition half-life (1.50 +/- 0.14 versus 0.81 +/- 0.04 h), lower systemic clearance (111.7 +/- 4.7 versus 279 +/- 12 ml/min) and renal clearance (78.7 +/- 4.3 versus 221 +/- 14 ml/min) of intact drug, and a slightly smaller steady-state volume of distribution (10.3 +/- 0.21 versus 12.8 +/- 0.48 liters). Mean recoveries of cefmetazole and cefoxitin in urine were approximately 71 and 77%, respectively. Pretreatment of volunteers with probenecid (1 g orally) significantly (P less than 0.05) increased concentrations of cefmetazole in serum 1 h after drug administration without significantly increasing maximum concentrations in serum. Mean areas under the concentration-time curve (466 +/- 27 versus 295 +/- 13 micrograms.h/ml) and terminal disposition half-lives (2.27 +/- 0.13 versus 1.50 +/- 0.14 h) of cefmetazole increased. Systemic clearance (72.1 +/- 4.0 versus 111.7 +/- 4.7 ml/min) and renal clearance (47.4 +/- 4.0 versus 78.7 +/- 4.3 ml/min) of intact antibiotic decreased. Mean recoveries (65.9 +/- 3.7 versus 71.0 +/- 3.2%) of intact cefmetazole in urine were not significantly (P > 0.05) different. Elimination of cefmetazole in urine was also significantly prolonged by probenecid, with substantial concentrations of cefmetazole (>/= 20 micrograms/ml) found in the 12- to 24-h urine collection for 14 to 16 volunteers. The results show that cefmetazole remains at clinically relevant concentrations (1 to 2 micrograms/ml) approximately twice as long as cefoxitin, that serum cefmetazole can be maintained longer at clinically significant concentrations with preadministration of probenecid, and that cefmetazole is partially eliminated by renal tubule secretion.

Adult↗