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PubMed1990

Organic anion transport in macrophage membrane vesicles.

Cells of the J774 mouse macrophage-like cell line possess organic anion transporter that transport fluorescent dyes such as Lucifer Yellow out of the cytoplasmic matrix of the cells; the dye is both sequestered in endosomes and secreted into the extracellular medium. Lucifer Yellow that is sequestered within endosomes is subsequently delivered to the lysosomal compartment. In the present studies we demonstrated that probenecid inhibited removal of Lucifer Yellow from the soluble cytoplasm and sequestration into membrane bound organelles by quantitating Lucifer Yellow fluorescence in both soluble and membrane-associated fractions of J774 cells. In addition, we examined the uptake of Lucifer Yellow into isolated subcellular organelles derived from J774 cells. Lucifer Yellow transport in the organellar fraction of J774 cell homogenates was temperature- and pH-dependent and did not require ATP. Subcellular organelles from J774 cells were fractionated into endosome- and lysosome-enriched fractions by Percoll density gradient centrifugation. Lucifer Yellow was preferentially taken up by vesicles of the endosome-enriched fraction, and this transport was inhibited by probenecid. These studies provide direct evidence that probenecid inhibits Lucifer Yellow transport out of the cytoplasmic matrix and into cytoplasmic vacuoles in J774 cells and that organic anion transport in isolated organelles derived from J774 cells occurs preferentially in endosome, rather than in lysosome-enriched fractions; they suggest that Lucifer Yellow is carried across membranes via a secondary active transport process that requires proton symptom or hydroxyl anion antiport.

Adenosine Triphosphate↗
PubMed1988

Effects of lead and niacin on tryptophan and serotonin metabolism.

Studies were conducted to investigate the effects of lead and niacin on tryptophan and serotonin metabolism in growing broiler chicks. A low-niacin basal diet based on soybean meal and glucose was supplemented with either 40 ppm niacin/kg feed or 2,000 ppm lead, as lead acetate trihydrate, or a combination of the two in a 2 x 2 factorial arrangement. The experimental diets were fed from 1 day to 3 weeks of age. The activities of several enzymes involved in tryptophan and serotonin metabolism were assayed in chicks fed each of the experimental diets. Lead reduced the activity of liver tryptophan pyrrolase but had no effect on the activity of hepatic picolinic carboxylase. Low dietary niacin had no effect on the activity of either of these enzymes. Brainstem tryptophan 5-hydroxylase activity was unaltered by either lead or niacin. Brain and liver monoamine oxidase activity was reduced by lead but was not affected by niacin. No interactions of lead and niacin were observed with any of the enzymes examined. Lead had no consistent effect on brain serotonin (5-HT) steady-state level, but it increased the level of the major metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA). Monoamine oxidase blockade failed to reduce the elevated 5-HIAA level in lead-treated chicks. The drug probenecid produced an increase in 5-HIAA that was comparable to the increase caused by lead. The effects of probenecid and lead were additive. It is concluded that lead significantly altered the activity of several enzymes involved with tryptophan metabolism, whereas the dietary niacin levels employed were without effect. Additionally, lead caused the accumulation of 5-HIAA in the brain, which appeared to result from inhibition of the probenecid-sensitive acid transport system.

Animals↗
PubMed1989

Pharmacokinetics of single doses of cefoperazone given by the intravenous and intramuscular routes to unweaned calves.

Cefoperazone pharmacokinetics were studied in unweaned calves. The antibiotic was administered to 10 calves intravenously, to eight calves intramuscularly at 20 mg kg-1 and to 10 calves intramuscularly at 20 mg kg-1 together with probenecid at 40 mg kg-1. Serum concentration versus time data were analysed by non-compartmental methods based on the statistical moment theory. The intravenous data were also fitted by a linear, open two-compartment model. The terminal halflife of cefoperazone was 127.9 +/- 28.2 min (mean +/- SD) after intravenous and 136.9 +/- 19.6 min after intramuscular administration. The t1/2 was increased to 257.3 +/- 127.3 min by the co-administration of probenecid. The total body clearance was 8.16 +/- 1.60 ml min-1 kg-1 and the volume of distribution at steady state was 0.713 +/- 0.167 litre kg-1. The mean residence time values were 87.2 +/- 10.6 min after intravenous and 140.3 +/- 20.6 min after intramuscular injection and were increased to 264.5 +/- 99.8 min by the co-administration of probenecid. The estimated mean absorption time was 53.1 min and the estimated bioavailability after intramuscular administration was 76.3 per cent. The minimal inhibitory concentration (MIC90) values of cefoperazone ranged from 0.5 to 2 micrograms ml-1 for Escherichia coli, salmonella groups C, D and E and Pasteurella multocida isolates. Salmonella group B strains appeared to be highly resistant to cefoperazone with MIC90 greater than 32 micrograms ml-1. There were no significant differences between the pharmacokinetic variables calculated by statistical moment theory or compartmental analysis indicating central compartment output of cefoperazone.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1989

Evaluation of allopurinol use in patients with gout.

The use of long-term allopurinol therapy in patients with gout was evaluated. A pharmacy computer printout was used to identify all outpatients for whom allopurinol had been prescribed during a six-month period in 1985 at a large Veterans Administration medical center. Medical records were reviewed to (1) classify patients as either having or not having definite indications for allopurinol treatment, (2) determine whether physicians had ordered roentgenographic and laboratory tests for presence of monosodium urate crystals, uric acid excretion, and renal function, and (3) identify gout-associated risk factors and disease entities that could cause hyperuricemia. A pharmacy record of all allopurinol and probenecid prescriptions for the six-month period was obtained, along with cost data. Of the 286 patients who received allopurinol, 32 received the drug for an indication that could not definitely be established as gout. Of the 254 remaining patients, only 45 (17.7%) had a definite indication for allopurinol use as defined by the pharmacy and therapeutics committee. Although pretreatment measurement of serum creatinine was common, only a few patients underwent joint aspiration, a 24-hour urine collection, or roentgenography of affected joints. Large proportions of the patients were found to have gout-associated risk factors. If the 209 patients without definite indications for allopurinol therapy had been treated with probenecid instead of allopurinol, the annual cost savings would have been about $3700. Most of the patients receiving allopurinol for gout could reasonably have been treated with a uricosuric agent such as probenecid at a lower cost. Generally, physicians did not use diagnostic tests optimally before prescribing allopurinol and did not attempt to modify risk factors for gout.

Allopurinol↗
PubMed1978

A study of the mechanism of transport of benzylpenicillin in the rat submaxillary gland.

In vitro studies performed on slices of rat submaxillary gland to evaluate uptake and efflux of 14C-benzylpenicillin (10(-6)M, 10(-5)M) showed that uptake of 14C-benzylpenicillin was not significantly altered by aeration with N2, addition of 10(-5)M CN- or 10(-3) M probenecid, or substitution of K2SO4 in place of NaCl in the KRT buffer to produce a depolarizing solution. Lowering the extracellular pH (pHe) resulted in increases rates of uptake and efflux, whereas increasing the pHe resulted in decreased rates. The in vivo uptake of penicillin into whole glands excised from rates treated in vivo was very similar to that seen in the slice preparation. However, addition of probenecid to salivary gland slices in vitro decreased the rate of effux. These data suggest that the movement of penicillin in the rat salivary gland may occur by a two-step mechanism: (1) passive exchange of penicillin into the gland dependent on the degree of dissociation of penicillin, and (2) active excretion of the drug from the gland by a transport mechanism similar to that of the kidney densitive to probenecid.

Animals↗
PubMed1985

Mechanism of renal concentration of technetium-99m glucoheptonate.

Seventy female Sprague-Dawley rats were studied to determine the mechanism of tubular localization and the effects of commonly encountered changes in hydration and acid-base balance on renal uptake and urinary excretion of technetium-99m glucoheptonate ([99mTc]GHA). The in-vivo protein binding and protein-free plasma clearance of [99mTc]GHA also were quantitated. Twenty additional rats were studied to determine the effects of PAH competition and probenecid blockade on renal uptake of [99mTc]dimercaptosuccinic acid (DMSA) in comparison with their effects on [99mTc]GHA localization. Kidney uptake of [99mTc]GHA averaged 11.17 +/- 0.49 (s.e.)% of the injected dose in control animals. This varied slightly among groups but was significantly reduced by probenecid blockade and para-aminohippuric acid (PAH) competition to 4.08 +/- 0.55 (p less than 0.005) and 2.39 +/- 0.14 (p less than 0.005), respectively. Technetium-99m DMSA was not affected in its renal accumulation by these maneuvers. The total plasma clearance of [99mTc]GHA was lower than iodine-125(125I)iothalamate but the clearance of the protein free supernate was higher, raising a possibility of some tubular secretion. Acidification of the urine which has been shown to reduce [99mTc]DMSA uptake appeared to have no effect on [99mTc]GHA. Hepatic uptake was minimal in all groups averaging less than 1% injected dose. These data demonstrate that renal accumulation of [99mTc]GHA is blocked by probenecid and PAH suggesting that it is actively concentrated in the proximal tubule by enzyme systems similar to those involved in PAH and hippuran transport. It appears that [99mTc]GHA uptake measures a different aspect of kidney function than [99mTc]DMSA.

Acid-Base Imbalance↗
PubMed1986

Clinical experience in the use of clavulanic acid/penicillin regimens in the treatment of uncomplicated gonorrhoea.

In an attempt to investigate the possibility of re-establishing the use of penicillins in the treatment of gonorrhoea in Singapore, a series of studies were conducted between 1981 and 1984, to evaluate the efficacy of a variety of penicillin-clavulanic acid combinations. A total of 6 different regimens were evaluated, and we concluded that 3 regimens consisting of 2 doses of Augmentin 3.25 g P.O., 4 hours apart (regimen C), aqueous procaine penicillin G (APPG) 4.5 mega units I.M. + Augmentin 375 mg + probenecid 1g P.O. (regimen E), and APPG 4.5 mega units I.M. + Augmentin 750 mg + probenecid 1g P.O. (regimen F) were very efficacious against infection due to PPNG and non PPNG. The cure rates obtained were 96.6% (regimens C and E), and 95% (regimen F) for infection due to PPNG and 95.6% (regimen C), and 100% (regimens E and F) for those due to non PPNG. Regimen E consisting of aqueous procaine penicillin G 4.5 meg units I.M. + Augmentin 375 mg + probenecid 1g P.O. was felt to be economical as well as effective against PPNG and non PPNG, and had the potential advantage of being effective against incubating syphillis. Regimen consisting 2 oral doses of Augmentin 3.25 g, 4 hours apart was an effective therapy for patients who preferred oral medication alone. However, this therapy was most costly. No serious side effects of treatment were observed with any of the regimens used.

Adult↗
PubMed1988

Fura-2 secretion and sequestration in macrophages. A blocker of organic anion transport reveals that these processes occur via a membrane transport system for organic anions.

Fura-2, loaded into J774.2 macrophages as the acetoxymethyl ester, is sequestered into intracellular vacuoles within 90 min after the beginning of the loading at 37 degrees C. The dye is also efficiently secreted from the cells. Sequestration and secretion of fura-2 reduce the accuracy of measurements of cytosolic free Ca2+ concentration in this cell line. Fura-2 is also sequestered and secreted by J774.2 when the dye is loaded into the cytoplasm as the pentapotassium salt by reversible permeabilization of the plasma membrane. Regardless of the mechanism by which fura-2 is loaded into the cytoplasm, both sequestration and secretion are prevented by 2.5 mM probenecid, a blocker of organic anion transport. Probenecid has no effect on resting or stimulated cytosolic free Ca2+ levels or on FcR-mediated phagocytosis. These findings suggest that macrophages express a transport mechanism for the anionic form of fura-2. This transport system is responsible for the clearance of fura-2 from the cytoplasm of this cell type. Furthermore we suggest that use of probenecid to block secretion and intracellular sequestration of fura-2 may overcome problems arising in the application of this Ca2+ indicator to macrophages and perhaps to other cell types.

Animals↗
PubMed1988

Metabolism and excretion of S-conjugates derived from hexachlorobutadiene in the isolated perfused rat kidney.

Renal processing of the S-conjugates derived from hexachlorobutadiene (HCBD), S-(pentachlorobutadienyl)glutathione (PCBG), and S-(pentachlorobutadienyl)-L-cysteine (PCBC) was studied in the isolated perfused rat kidney. At an initial perfusate concentration of 20 microM, both conjugates were rapidly eliminated from the perfusate. Calculation of the fractional clearance rates revealed the dominant role of nonfiltering mechanisms in this process. This was confirmed by the strong inhibitory effect of 50 microM probenecid. S-(Pentachlorobutadienyl)-N-acetyl-L-cysteine (N-Ac-PCBC) was detected as the major metabolite of both PCBG and PCBC in urine and perfusate. PCBC and S-(pentachlorobutadienyl)cysteinylglycine were minor urinary metabolites formed from PCBG; only N-Ac-PCBC and PCBC were detected in the perfusate. At an initial S-conjugate concentration of 100 microM in the perfusate, the rate of elimination of both PCBG and PCBC continuously decreased during the perfusion, mainly as the result of a reduced excretion of N-Ac-PCBC. This indicates marked disturbance of N-acetylation and/or transport under these conditions. Addition of probenecid resulted in a significantly reduced renal elimination of both S-conjugates, predominantly due to a reduced rate of mercapturate excretion. In contrast, the nephrotoxicity of PCBC or PCBG was not significantly influenced by probenecid. It is concluded from these experiments that the kidney has the capacity to metabolize HCBD S-conjugates and that nonfiltering excretion of the mercapturic acid plays a decisive role. The pathways of HCBD S-conjugate metabolism in the kidney were shown to be dependent on their initial concentrations in the perfusate, most probably as a consequence of concentration-dependent toxic disturbances of transport and/or N-acetylation.

Acetylation↗
PubMed1979

Safety of tienilic acid.

The safety and efficacy of tienilic acid have been evaluated in studies of patients with mild to moderate essential hypertension, salt and water retention states and hyperuricaemia associated with gout. During the course of these studies 675 patients were treated with tienilic acid, 310 were treated with hydrochlorothiazide, 43 were treated with probenecid and 34 were treated with placebo. Overall, adverse reactions characterized as probably drug-related or questinably drug-related were reported in 28% of patients treated with tienilic acid, 24% treated with hydrochlorothiazide, 25% of patients treated with probenecid and 33% treated with placebo. The side effects encountered were mild in severity, reversible and represented extensions of the pharmacological activity of tienilic acid, hydrochlorothiazide and probenecid. These initial studies demonstrate that tienilic acid is safe and effective in the treatment of mild to moderate essential hypertension, salt and water retention states, including oedema associated with congestive cardiac failure or mild to moderate renal dysfunction, and in the management of elevated serum uric acid levels associated with gout.

Clinical Trials as Topic↗
PubMed1979

Hypouricemia by defect in the tubular reabsorption.

Two patients with hypouricemia with high levels of uric acid in their urine were given pyrazinamide and probenecid. The uric acid clearance decreased to low or normal values after pyrazinamide administration. In both cases, probenecid produced a slight increment in the uric acid excretion. This type of response suggests a defect in the reabsorption component. It is tempting to speculate on a postsecretory reabsorption defect based on the results of pyrazinamide and probenecid tests.

Absorption↗
PubMed1983

[Results of a comparative therapeutic trial of single-dose treatment of non-complicated acute male gonorrhea].

A single dose treatment trial with: spectinomycine 2 g, ampicilline + probenecide 3.5 g + 1 g, thiamphenicol 2.5 g, minocycline 300 mg was undertaken. Three teams were involved, epidemiologists clinicians, microbiologists, 636 patients were included, 483 resumed for control. A negative culture on the third day was considered a success. Failure rates were: spectinomycine 4%, ampicilline-probenecide 3%, thiamphenicol 4%, minocycline 3%. No significant difference was noted between the four rates. The delay of clinical cure was 1.98 days for spectinomycin, 1.87 days for ampicilline - probenecide, 2.16 days for thiamphenicol and 2.12 for minocycline without significant difference. When side effects were analysed, 10% of the patients reported asthenia without difference between the four treatments. Thiamphenicol is responsible for diarrhea 28%, P less than 0,01 minocycline more significantly responsible for guidiness 13%, P less than 0,001, and 18% treated by spectinomycine complained of pain at the time of injection. The antibiotics MIC's are studied. After the analysis of the results, the cost, and the resistances, one treatment was selected.

Ampicillin↗
PubMed1978

[The effect of benzbromarone on fasting-hyperuricemia as a model (author's transl)].

The effect of daily therapeutic doses of 100 mg benzbromarone (Normurat) and 2.0 g probenecid on the purine metabolism of 40 test subjects was investigated. Fasting-hyperuricemia was used as the model and particular attention paid to the mechanisms of renal elimination. Urate concentration remains under the solubility threshold when benzbromarone is administered, in contrast to medication with probenecid. The significantly greater hypouricemic effect of benzbromarone correlates with a significant rise in the excretion and clearance of uric acid in comparison to probenecid, accompanied by a stronger depression of tubular reabsorption. Serum levels, clearances and reabsorption rates demonstrate the prolonged effect of the benzofurane derivative Normurat even during strict fasting. Supplementary allantoin and urea determinations gave no indication of increased enterobacterial uricolysis. Normurat was well tolerated, side effects were not noted.

Adolescent↗
PubMed1982

Comparative accumulation of uric acid and hypoxanthine by slices of avian renal cortex.

The purpose of the study was to compare the concentrative uptake processes of the 14C-labeled purines uric acid (UA) and hypoxanthine (HX) by slices of chicken renal cortex. It was found that both purines were accumulated by the slices and that, while UA was unaltered metabolically, HX was partially oxidized to UA during the incubation. Inhibition of the oxidation of HX to UA by use of the enzyme inhibitor allopurinol did not alter accumulation indicating that metabolism of HX did not drive accumulation. UA accumulation was eliminated by the presence of low concentrations of the organic anion transport inhibitors probenecid and 4-acetamido-4'-isothiocyano-stilbene-2,2'-disulfonic acid. However, HX accumulation was unaffected by probenecid and significantly decreased by 4-acetamido-4'-isothiocyano-stilbene-2,2'-disulfonic acid only at concentrations considerably in excess of those needed to eliminate UA accumulation. The lack of effect of probenecid is in contrast to its reported inhibitory action on HX excretion by the chicken in vivo, a difference which may reflect lack of luminal transport by in vitro slices. Neither was HX accumulation sensitive to the presence of high concentrations of the organic cations quinine and tetraethylammonium. Despite the insensitivity of the HX accumulation process to organic anions or cations, the process was blocked by cyanide and an N2 atmosphere indicating energy dependence. The results suggest that both UA and HX are accumulated by separable transport processes indicating that the renal tubules possess more than one system capable of contributing to purine excretion.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1976

[Treatment of hyperlipemia and hyperuricemia with 2-acetamidoethyl-(4-chlorophenyl)-(3-trifluoromethylphenoxy)-acetate (halofenate), a derivative of clofibrate].

23 patients with hyperlipidemia and hyperuricemia received acetamidoethyl-(4-chlorophenyl)-(trifluoromethylphenoxy)-acetate (halofenate), a clofibrate derivative, and probenecid or probenecid and placebo over 36 weeks following a placebo period of 6 weeks. Halofenate compared with probenecid lowered elevated serum uric acid levels satisfactorily to a therapeutic level between 5 and 6 mg/100 ml. Serum triglyceride levels were not always lowered sufficiently, serum cholesterol levels were not influenced.

Cholesterol↗
PubMedDate not supplied

Release of cyclic nucleotides from the apical and basolateral poles of cultured human glomerular epithelial cells.

We have examined the intracellular accumulation and the release of cGMP and cAMP from the apical and basolateral poles of SV40-transformed human glomerular visceral epithelial cells (HGVEC) cultured on filters. After treatment of the cells by atrial natriuretic peptide (ANP), cGMP did not accumulate in the cells and was rapidly released mainly into the apical medium (86% of its total secretion). Its apical secretion was inhibited by 83% in the presence of probenecid, an organic acid transport inhibitor, and by 90% in the presence of nocodazole, a microtubule disrupter. cAMP was released more slowly than cGMP after it had accumulated in the cells. Apical polarization of the secretion still existed but was less marked than for cGMP (70% of its total secretion). Similarly, probenecid and nocodazole inhibited to a lesser degree cAMP egression (66 and 33%, respectively, for the apical secretion). Polarization of HGVEC was confirmed by the vectorialized secretion of lactate dehydrogenase. These results indicate that cGMP release from HGVEC is essentially apical and depends on a probenecid-sensitive organic acid transport and also on an intact microtubular network. cAMP release appears to be less polarized and less sensitive to the two drugs studied. Vectorially secreted cGMP in the urinary space in response to ANP could act downstream in the nephron and thus permit ANP to stimulate cells which do not necessarily possess ANP receptors.

Cell Line, Transformed↗
PubMed1993

Treatment of gonorrhea in pregnancy.

OBJECTIVE: To evaluate prospectively the 1989 Centers for Disease Control recommendations for treatment of gonorrhea in pregnancy. METHODS: Two hundred fifty-two women referred with probable endocervical gonorrhea had pre-treatment endocervical, rectal, and oral cultures for Neisseria gonorrhoeae and direct fluorescent antibody testing for Chlamydia trachomatis. They were assigned randomly to receive ceftriaxone 250 mg intramuscularly (IM), spectinomycin 2 g IM, or amoxicillin 3 g orally plus probenecid 1 g orally. Treatment was unblinded and in a 1:1:1 distribution. RESULTS: Two hundred forty-five women (97%) had endocervical infection, 68 (27%) had rectal infection, and 17 (7%) had pharyngeal infection. One hundred two of 252 women (40%) had concomitant endocervical C trachomatis. The overall efficacy was 235 of 252 subjects (93%) (95% confidence interval [CI] 90.1-96.4%). Ceftriaxone was effective in 80 of 84 cases (95%) (95% CI 90.6-99.9%), amoxicillin with probenecid was effective in 75 of 84 cases (89%) (95% CI 82.5-96%), and spectinomycin was effective in 80 of 84 cases (95%) (95% CI 90.6-99.9%). No significant difference was noted in overall efficacy or by site of infection. There was no increased incidence of congenital malformations in the offspring spring of any treatment group. CONCLUSIONS: Ceftriaxone and spectinomycin are safe and effective for the treatment of gonorrhea in pregnancy. Amoxicillin with probenecid has lower efficacy and is not recommended for treatment of gonococcal infection in pregnancy.

Adult↗
PubMed1977

Prostaglandin F in patients with primary affective disorder.

Two aspects of prostaglandin F (PGF) metabolism were assessed in patients with primary affective disorder. For a group of hospitalized patients cerebrospinal fluid PGF was measured by radioimmunoassay and the effects of probenecid and L-tryptophan were determined. For outpatients attending our Lithium Clinic, plasma PGF was measured and the acute and chronic effects of lithium were determined. The results of the studies reveal apparently normal concentrations of PGF in cerebrospinal fluid. These concentrations increase twofold after probenecid, indicating that PGF is transported out of the central nervous system by a probenecid-sensitive active transport system. Evidence for inhibition of PGF synthesis during L-tryptophan treatment was found. The results for outpatient plasma studies suggest no effect on PGF with 12 weeks of lithium treatment, although a slight elevation of plasma PGF with chronic lithium treatment may occur. Specificity of the assay technique as applied to plasma is discussed. This is the first report of the direct measurement of PGF in a psychiatric disorder.

Adult↗