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At least 1,153 records · Page 64Linked to original sources
PubMed1987

Drug interactions with urate excretion in man.

The effects of pyrazinamide and ampicillin on the uricosuric response to probenecid and benzbromarone were studied in six normal subjects. The amount of uric acid was calculated for the 24 h volume of urine and the urate and creatinine clearances were determined for each of three urinary collection periods in order to calculate the percentage Curate/Ccreatinine. Ampicillin alone caused a significant uricosuria in the 0-2 h (p less than 0.025) and 8-24 h (p less than 0.025) periods. Benzbromarone caused a significant reduction in all the parameters. These observations suggest that high concentrations ampicillin compete with uric acid for reabsorption, but that its delayed uricosuric action can be ascribed to the binding of this dipeptide to a charge-mediated receptor site on the brush border membrane of proximal tubular cells. It would also appear that benzbromarone is secreted by the pyrazinamide-sensitive mechanism for urate secretion as it can cause a paradoxical retention of urate, but leaves the other probenecid-sensitive secretory transport process unoccupied as indicated by the fact that it does not change the kinetics of ampicillin.

Adult↗
PubMed1994

Active cell membrane mechanisms involved in the exclusion of Rh 123 allow distinction between normal and tumoral cells.

Human cell lines derived from three epithelial carcinomas (CaSki, HeLa, SiHa), one B lymphoma (BL60), one promyelocytic (HL60), one monocytic (U937) leukemia, one chronic myelogenous leukemia (sensitive K562S; multichemoresistant K562R) and normal human skin fibroblasts were compared for their capacity of staining with rhodamine 123 (Rh 123) and their kinetics of dye exclusion. Cells were exposed for 30 min to 10 micrograms/ml of Rh 123 in culture medium; fluorescence intensity was measured by flow cytometry immediately or 1, 2, 3 and 4 h after staining. The highest fluorescence intensity was observed in carcinoma cell lines; there was no incorporation in multichemoresistant K562R cells. Exclusion of Rh 123 was evaluated from 0 to 4 h, both by flow cytometry and by fluorimetry. Fluorescence intensity measured by flow cytometry decreased slightly in carcinoma and leukemia cells and rapidly in fibroblasts. In all cell lines Rh 123 exclusion was inhibited by 40 mumol/L verapamil and 5 mmol/L probenecid. Thus, incorporation and exclusion of Rh 123 allows distinction between normal and tumoral cells; moreover, inhibition of exclusion by verapamil and probenecid favors the involvement of active cell membrane mechanisms in the exclusion process.

Cell Membrane↗
PubMed1982

Accumulation, elimination, release and metabolism of pipecolic acid in the mouse brain following intraventricular injection.

Following i.c.v. (intracerebral ventricular) injections of D,L-[3H]pipecolic acid (PA), it is reabsorbed from the ventricles and redistributed to various brain regions. The highest accumulation is found in three brain regions ipsilateral to the injection site, hippocampus, neocortex, striatum, and in the diencephalon. Following preloading in vivo, the radioactivity is released from hippocampus slices in the perfusion medium after depolarization induced by high K+. During perfusion with a Ca++ free medium containing EGTA, a significant reduction of release is observed. The radioactivity of D,L-[3H]PA in the brain shows a more rapid phase of decrease from 0 to 2 hours and a slower phase from 2 to 5 hours. At 5 hours, only 28% radioactivity, represented mainly by PA, is left in the brain. Kidney secretion represents the major route of elimination of the injected PA. The presence of alpha-aminoadipic acid both in brain and urine was observed. Probenecid (200 mg/kg) significantly increases the accumulation of i.c.v. injected D,L-[3H]PA in brain and kidney. The presence of a regional accumulation of PA in certain brain regions, its metabolism in brain, its enhanced retention following probenecid administration and its Ca++ dependent release following high K+ stimulation, all constitute indirect evidence for a neuronal localization of this brain endogenous aminoacid.

Animals↗
PubMed1985

The human pharmacokinetics of cefotaxime and its metabolites and the role of renal tubular secretion on their elimination.

The pharmacokinetics of cefotaxime were investigated in human volunteers given constant intravenous infusions, intravenous bolus, and intramuscular doses of the drug. After intravenous dosing, the plasma levels of cefotaxime declined in a biphasic manner with a terminal half-life varying between 0.92 and 1.65 hr. Moreover, the pharmacokinetics were linear up to at least a 2.0 g dose for volume of distribution based on area (23.3-31.3 l), plasma clearance (249-2.88 ml/min), and renal clearance (151-177 ml/min). Renal tubular secretion of intact cefotaxime and each of its metabolites was demonstrated by its interaction with probenecid, although the ratio of drug to metabolites ultimately excreted in urine after probenecid was similar to that seen normally (54 +/- 6, 19 +/- 4, 6.5 +/- 0.7 and 5.5 +/- 0.7% for cefotaxime, DACM, M2, and M3, respectively, when calculated as a percentage of the dose). The observed half-lives of DACM, M2, and M3 were 2.3 +/- 0.4, 2.2 +/- 0.1 and 2.2 hr, respectively. However, when the true half-life of DACM was calculated (0.83 +/- 0.23 hr) it was not only significantly shorter than that observed but also shorter than that for intact cefotaxime. The plasma clearance of DACM (744 +/- 226 ml/min) was much higher than that of cefotaxime while the volume of distribution was of a similar order (56 +/- 24 l). When administered intramuscularly, there was good absorption of cefotaxime from the site of injection (92-94%) giving maximum plasma levels of the drug of between 30 and 35 mg/l at approximately 40 min after dosing. Thereafter, the plasma levels of cefotaxime declined in a monophasic manner with a half-life (1.0-1.2 hr) similar to that of the terminal half-life seen after intravenous administration. Lidocaine had no significant effect on either its absorption or elimination kinetics.

Adult↗
PubMed1977

Brain tyrosine level controls striatal dopamine synthesis in haloperidol-treated rats.

Animals received either haloperidol (2 mg/kg) or probenecid (200 mg/kg) in conjunction with tyrosine (100 mg/kg) or its diluent. Striatal homovanillic acid levels increased in probenecid-treated animals to the same range whether they were given tyrosine or not. In haloperidol-treated animals the levels of homovanillic acid were significantly elevated in animals receiving tyrosine. Tyrosine and homovanillic acid levels were highly correlated as determined by linear regression analysis.

Animals↗
PubMed1979

A dose response study with bacampicillin in uncomplicated gonorrhoea.

In a systematic study of dose-response relationship 883 patients with uncomplicated gonorrhoea were given single oral doses of 400, 800 or 1600 mg bacampicillin, with 1 g probenecid. A single dose of bacampicillin 800 mg plus probenecid was the minimum effective dose in patients with fully ampicillin-sensitive strains. In patients with gonococci showing reduced sensitivity to ampicillin, 1600 mg bacampicillin was required to reach a cure rate above 95%. Bacampicillin was well tolerated in all treatment groups. Side-effects were reported in 4.6% of the courses of treatment. The most frequent adverse reaction was loose stools (1.9%), which was noted more often after the 1600 mg dose but was considered to be of no or very little clinical importance.

Administration, Oral↗
PubMed1998

Comparison of oral cefixime and intravenous ceftriaxone followed by oral amoxicillin in disseminated Lyme borreliosis.

Two treatment regimens for disseminated Lyme borreliosis (mainly neurologic and musculoskeletal manifestations) were compared in a randomized trial. A group of 30 patients received oral cefixime 200 mg combined with probenecid 500 mg three times daily for 100 days. Another group of 30 patients received intravenous ceftriaxone 2 g daily for 14 days followed by oral amoxicillin 500 mg combined with probenecid 500 mg three times daily for 100 days. There was no statistically significant difference in the outcome of infection between the two groups. However, the total number of patients with relapses or no response at all and the number of positive polymerase chain reaction findings after therapy were greater in the cefixime group. The general outcomes of infection in patients with disseminated Lyme borreliosis after 3-4 months of therapy indicate that prolonged courses of antibiotics may be beneficial in this setting, since 90% of the patients showed excellent or good treatment responses.

Administration, Oral↗
PubMed1975

Hyperuricosuria and increased tubular secretion of urate in sickle cell anemia.

Seven young adults with uric acid overproduction due to sickle cell anemia were normouricemic with a mean serum uric acid level of 4.9 mg/100 ml. Urate clearance was greater in these patients than in normal subjects or in patients with primary hyperuricemia due to uric acid overproduction. The increase in urate clearance was entirely accounted for by increased pyrazinamide suppressible urate clearance. Pyrazinamide administration abolished the uricosuric response to ribonucleic acid (RNA) feeding in these patients with sickle cell anemia, and maximal uricosuric response to the administration of probenecid was similar in the patients with sickle cell anemia and in normal subjects suggesting that reabsorption of both filtered and secreted urate was not impaired in sickle cell disease. Pyrazinamide suppressible urate clearance at maximal uricosuric response to probenecid was increased in patients with sickle cell disease suggesting increased tubular secretion of urate. This increase in urate secretion permits most young adults with urate overproduction due to sickle cell anemia to remain normouricemic and may account for the low frequency of secondary gout in this disease.

Adolescent↗
PubMed1992

Inhibition of organic anion transport in endothelial cells by hydrogen peroxide.

ATP loss is a prominent feature of cellular injury induced by oxidants or ischemia. How reduction of cellular ATP levels contributes to lethal injury is still poorly understood. In this study we examined the ability of H2O2 to inhibit in a dose-dependent manner the extrusion of fluorescent organic anions from bovine pulmonary artery endothelial cells. Extrusion of fluorescent organic anions was inhibited by probenecid, suggesting an organic anion transporter was involved. In experiments in which ATP levels in endothelial cells were varied by treatment with different degrees of metabolic inhibition, it was determined that organic anion transport was ATP-dependent. H2O2-induced inhibition of organic anion transport correlated well with the oxidant's effect on cellular ATP levels. Thus H2O2-mediated inhibition of organic anion transport appears to be via depletion of ATP, a required substrate for the transport reaction. Inhibition of organic anion transport directly by probenecid or indirectly by metabolic inhibition with reduction of cellular ATP levels was correlated with similar reductions of short term viability. This supports the hypothesis that inhibition of organic anion transport after oxidant exposure or during ischemia results from depletion of ATP and may significantly contribute to cytotoxicity.

Adenosine Triphosphate↗
PubMed1976

The inhibitor effect of probencid and structural analogues on organic anions and chloride permeabilities in ox erythrocytes.

Probenecid inhibits anion movements (organic anions and chloride) in ox erythrocytes. The I50 is 4. 10(-5) M. Structural analogues such as carinamide, p-carboxybenzene sulfonamide and p-carboxy N,N-diethyl benzene sulfonamide, which are drugs of the sulfonamide class, were also found to inhibit anion transport. These results reinforce the previously discussed view based on structural considerations, that sulfonamides act on the red cell membrane as competitors of anion transport. It is possible that probenecid and carinamide act in a similar way in the kidney.

Animals↗
PubMed1982

Mechanisms of p-aminohippurate transport by brush-border and basolateral membrane vesicles isolated from rat kidney cortex.

The uptake of [3H]-labeled p-aminohippurate by brush-border and basolateral membrane vesicles isolated from rat renal cortex has been studied by a rapid filtration technique. Some characteristics of carrier-mediated transport for p-aminohippurate were demonstrated in basolateral membrane vesicles: the uptake was inhibited by probenecid or 4,4'-diisothiocyano-2,2'-disulfonic stilbene (DIDS), was saturable, was stimulated by the countertransport effect, and showed discontinuity in the Arrhenius plot. In contrast, brush-border membrane vesicles failed to display saturability of p-aminohippurate uptake and stimulation by the countertransport effect, although probenecid and DIDS reduced the uptake. Furthermore, p-aminohippurate uptake by brush-border membrane vesicles was influenced more sensitively by alteration in the membrane potential compared with that by basolateral membrane vesicles.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1985

Alloxan stimulates p-aminohippurate uptake in renal basal-lateral membranous vesicles.

In renal basal-lateral membranous vesicles, the probenecid-sensitive p-aminohippurate uptake was stimulated by alloxan. This stimulation of uptake was observed only after a lag period of 15 seconds, and it reached a maximal value after one minute. Stimulation was increased by 1 mM to 5 mM alloxan in a linear fashion. The effect was maximal and constant between 5 mM and 20 mM alloxan. Alloxan affected neither the glucose space of the vesicle nor the rate of transport or diffusion of glutamate, another organic anion. The mechanism of stimulation by alloxan was not clear. Its effect was blocked by the sulfhydryl reagent N-ethylmaleimide and weakly mimicked by H2O2, an oxidizing reagent. However, ninhydrin, a structural analogue of alloxan which reacts with sulfhydryl groups, and glucose, a neutral structural analogue of alloxan, failed to stimulate probenecid-sensitive uptake.

Alloxan↗
PubMed1993

Altered expression of unidirectional extrusion routes for methotrexate and cholate in an efflux variant of L1210 cells.

The specificity and function of two unidirectional anion-efflux pumps in mouse L1210 cells were evaluated using a variant cell line selected for growth in the presence of cholate and bromosulfophthalein. Transport analysis revealed that cholate efflux in the variant L1210/C7 cell line had declined 8-fold, due to the loss of a bromosulfophthalein-sensitive efflux system, the major extrusion route for cholate in parental cells. Efflux measurements showed further that a bromosulfophthalein-sensitive efflux system for methotrexate was also absent in L1210/C7 cells. Total unidirectional efflux of methotrexate, however, was similar in the variant and parental cells, since the loss in the bromosulfophthalein-sensitive system was compensated by a rise in a second probenecid-sensitive route. The latter was identified from inhibitor studies to be the same system which acts as a minor efflux route for methotrexate in parental cells. These results support the hypothesis that L1210 cells contain a bromosulfophthalein-sensitive efflux system which mediates the unidirectional extrusion of either methotrexate or cholate, and a second probenecid-sensitive route which differs from the bromosulfophthalein-sensitive system in inhibitor specificity and also in its ability to transport methotrexate but not cholate.

Animals↗
PubMed1983

Evidence for the active renal secretion of S-pentachlorophenyl-N-acetyl-L-cysteine by female rats.

Male and female rats received 50 mumoles of pentachloronitrobenzene/kg by oral intubation daily for seven days. The final excreta were hydrolysed and analysed by electron capture GLC for the presence of pentachlorobenzenethiol and tetrachloro-1,4-benzenedithiol (derived from the equivalent N-acetylcysteine conjugates). No differences were found between the sexes for faeces and bile but the urinary excretion of both thiols by females was more than 10-fold greater than males. A similar result for urine was obtained following i.p. administration of a single 20 mumoles/kg dose of S-pentachlorophenyl-N-acetyl-L-cysteine (pentachlorophenyl mercapturate); in addition co-treatment with probenecid did not greatly change excretion by the males but considerably reduced excretion by females. The sex difference in the urinary levels of pentachlorophenyl N-acetylcysteine after 40 and 100 mumoles/kg doses of pentachloronitrobenzene was confirmed by h.p.l.c. of the mercapturate and again probenecid inhibited the excretion. Analysis of urine by TLC following a dose of [14C]hexachlorobenzene (8 muCi/kg; 0.67 mumoles/kg) showed that more radioactivity was associated with the mercapturate from female rats than males. The results suggest that S-pentachlorophenyl-N-acetyl-L-cysteine, a metabolite of hexachlorobenzene and pentachloronitrobenzene, may be excreted by an active renal secretion which is particularly developed in female F344 rats.

Acetylcysteine↗
PubMed1989

Effects of five anion channel blockers on thrombin- and ionomycin-activated platelet functions.

The inhibitory effects of anion channel blockers were evaluated on aggregation, intracellular Ca2+ rises, and the production of arachidonic acid metabolites in human platelets. Inhibitors included five anion channel blockers: phloretin, probenecid, pyridoxal phosphate, 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS) and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS). The degree of inhibition by each of these agents was dose-dependent on thrombin-activated platelet function. These agents generally had no significant inhibitory effects on ionomycin-activated platelet functions. It is suggested that anion mobilization plays a major role in the receptor-mediated activation of platelet functions, but only a minor role in Ca2+ ionophore-induced platelet activation. It is also suggested that several agents may have properties unrelated to anion channel blockers. Phloretin may be a selective cyclooxygenase inhibitor, and probenecid may inhibit phospholipase A2. DIDS and SITS may interfere with certain aggregation-inducing mechanisms.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1995

Hepatic uptake and biliary excretion of the neuroprotectant 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)-quinoxaline in rat liver. Involvement of an organic anion transport system.

The hepatic uptake and biliary excretion of the neuroprotective drug 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(f)-quinoxaline (NBQX) was studied in rat liver. In the isolated single-pass perfused rat liver preparation NBQX was infused in protein-free Krebs-Henseleit bicarbonate buffer at input concentrations ranging from 0.5 to 15 microM. The hepatic uptake could be characterized as a pseudo first-order unidirectional process with an apparent half-life of 5.8 min. Significantly higher concentrations of NBQX were measured in bile compared to perfusate with a maximal ratio at the lowest input concentration (approx. 2400-fold). Hepatic uptake and biliary excretion of NBQX exhibited saturation at increasing input concentrations, indicating an active transport mechanism. The uptake process could be described by Michaelis-Menten kinetics resulting in a Km,uptake of 2.2 microM. The corresponding maximal uptake rate (Vmax,uptake) was calculated to be 103 nmol/min. The maximal biliary excretion rate was estimated to be 58 nmol/min. The rate-limiting factor in the overall hepatic elimination was thus biliary excretion. Co-infusion with the uricosuric drug probenecid resulted in significantly decreased hepatic uptake and biliary excretion. These data suggest that NBQX is eliminated by an organic anion transport system in rat liver which is sensitive to probenecid.

Animals↗
PubMed1994

Mechanism of methylmercury efflux from cultured astrocytes.

To study the mechanism of methylmercury (MeHg) efflux from the central nervous system cells, cultured astroglia obtained from neonatal rats were incubated with 10 microM MeHg-cysteine (CySH) for 30 min. After being washed four times, cells were incubated in Hg-free medium, and the release of MeHg from the cells was monitored. The amount of MeHg released in the medium approached a plateau level (ca. 31% of the loaded amount) at 4 hr. Treatment of the cells with a CySH precursor, 2-oxothiazolidine-4-carboxylic acid (OTC), resulted in a significant increase of cellular levels of CySH and glutathione (GSH). OTC also increased 1.5-fold the MeHg efflux from the loaded cells. Another GSH enhancer, GSH isopropyl ester, also stimulated MeHg export from the cells. Ion-exchange column chromatography using DEAE-Sephadex revealed that the MeHg metabolite thus released was exclusively MeHg-GSH conjugate, both with and without OTC. Since the MeHg efflux was suppressed significantly by the presence of probenecid, the efflux occurred via the probenecid-sensitive organic acid transport system. Even though the cellular GSH levels were depleted drastically by treatment with L-buthionine-(S,R)-sulfoximine (BSO), a considerable level (90% of the control) of Hg efflux was detected. Since neither GSH- nor CySH-MeHg was detected in the culture medium of the BSO-treated cells, GSH depletion may trigger some other secretion system(s) in the cells. These results suggest that conjugation with GSH is the major pathway for MeHg efflux in rat astroglia, and that elevation in the cellular GSH level would possibly be a logical therapy for MeHg poisoning, promoting the accelerated elimination of MeHg from the critical tissues.

Animals↗
PubMed1976

The effect of trauma on the activity of central noradrenergic neurones.

Changes in the concentration of the main noradrenaline metabolite in rat brain, 4-hydroxy-3-methoxy-phenylethyleneglycol sulphate (MOPEG-SO4) have been studied during and after injury by limb ischaemia. In the hypothalamus the MOPEG-SO4 concentration rose in about 30 min to a new plateau level which was maintained during a 4 h period of bilateral hind-limb ischaemia and then rose further when the circulation to the limbs was restored. After about 2 h hind-limb ischaemia the concentration in the hind-brain, particularly in the caudal half, rose progressively and this rise continued when the tourniquets were removed after 4 h. Limb ischaemia did not affect the MOPEG-SO4 concentration in the cerebellum but the concentration rose in the cerebrospinal fluid. Attempts to study the production of MOPEG-SO4 in more detail by inhibiting its transport from the brain with probenecid were not helpful and reasons are given for thinking that probenecid is not a useful tool for this type of investigation. The results are considered to provide further evidence that trauma activates ascending and descending pathways which arise from the noradrenergic nerve cells in the hind-brain.

Animals↗