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PubMed2002

The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies.

Oseltamivir is an ester prodrug of the active metabolite [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), a potent and selective inhibitor of neuraminidase enzyme of influenza virus. Oseltamivir is rapidly hydrolyzed by hepatic carboxylesterases to Ro 64-0802, which is then exclusively excreted by glomerular filtration and active tubular secretion without further metabolism. In vivo and in vitro studies were conducted to evaluate the renal drug-drug interaction potential of oseltamivir. Crossover studies were conducted in healthy subjects in which oral oseltamivir was administered alone and coadministered with probenecid, cimetidine, or amoxicillin. Probenecid completely blocked the renal secretion of Ro 64-0802, increasing systemic exposure (area under the curve) by 2.5-fold, but no interaction was observed with cimetidine or amoxicillin. These in vivo data show that Ro 64-0802 is secreted via an organic anion pathway, but Ro 64-0802 does not inhibit amoxicillin renal secretion. In vitro effects of Ro 64-0802 on the human renal organic anionic transporter 1 (hOAT1) were investigated using novel Chinese hamster ovary cells stably transfected with hOAT1. Ro 64-0802 was found to be a low-efficiency substrate for hOAT1 and a very weak inhibitor of hOAT1-mediated transport of p-aminohippuric acid (PAH). Ro 64-0802 did not inhibit the hOAT1-mediated transport of amoxicillin. In contrast, probenecid effectively inhibited the transport of PAH, Ro 64-0802, and amoxicillin via hOAT1. These in vitro observations are consistent with the in vivo data, validating the usefulness of the in vitro system for evaluating such drug-drug interaction. The study results demonstrate that oseltamivir has a low drug-drug interaction potential at the renal tubular level due to inhibition of hOAT1.

Acetamides↗
PubMed1980

Serum and subcutaneous chamber fluid dynamics of penicillins after single large parenteral doses.

Serum and subcutaneous chamber fluid (CF) dynamics of penicillin G, ampicillin, and amoxicillin were studied in rabbits after single large parenteral doses comparable to doses used in treating gonorrhea and endocarditis. The effects of parenteral probenecid and of injection of an antibiotic directly into a subcutaneous chamber ("intrachamber" injection) also were studied. Peak serum antibiotic concentrations exceeded peak CF concentrations and occurred sooner. Antimicrobial activity persisted longer in CF than in serum. Percent penetration [100 x (CF peak/serum peak)] of CF was least after intramuscular ampicillin and amoxicillin, was greatest after intrachamber ampicillin and intramuscular aqueous procaine penicillin G, and was related to duration of antibiotic concentration gradients from serum to CF. Intramuscular aqueous crystalline penicillin G resulted in higher serum and CF penicillin G concentrations than intramuscular aqueous procaine penicillin G, which prolonged the duration of penicillin G in serum and CF. Amoxicillin diffused into CF more readily than ampicillin. Probenecid resulted in higher early serum and CF antibiotic concentrations, but had little or no effect on duration of antibiotic activity. Intrachamber ampicillin resulted in more prolonged serum and CF ampicillin activity than intramuscular ampicillin, but much lower peak serum concentrations. The data suggest a possible means by which probenecid improves the efficacy of gonorrhea therapy with aqueous procaine penicillin G. Intrachamber administration of penicillins could be useful in treating experimental infections requiring prolonged therapy.

Amoxicillin↗
PubMed1987

Mechanism of renal excretion of carumonam in rats, rabbits, dogs, and monkeys.

The mechanism of the renal excretion of carumonam (CRMN) was investigated in rats, rabbits, dogs, and monkeys. Stop-flow analysis in dogs demonstrated that CRMN is exclusively excreted by glomerular filtration. There was no specific CRMN peak corresponding to the peak of p-aminohippuric acid (PAH) secretion or to the trough of Na+-K+ reabsorption in the stop-flow pattern. Although the PAH peak disappeared when probenecid was administered, the CRMN stop-flow pattern showed no change. In rabbits, however, the CRMN concentration peak corresponding with the PAH peak was detected in the stop-flow pattern; the CRMN peak disappeared when probenecid was administered. The pharmacokinetic parameters in plasma, such as the area under the concentration-time curve, the half-life, and the clearance rate, were affected by probenecid in rats, rabbits, and monkeys, but not in dogs. The results suggest that the renal excretion of CRMN in dogs takes place exclusively through glomerular filtration. In rats, rabbits, and monkeys, however, CRMN is excreted through both glomerular filtration and renal tubular secretion.

Animals↗
PubMed2004

Active efflux of ciprofloxacin from J774 macrophages through an MRP-like transporter.

The accumulation and efflux kinetics of ciprofloxacin have been examined by using murine J774 macrophages. Accumulation (at equilibrium) was increased (three- to fourfold) (i) when cells were incubated with high extracellular drug concentrations (typically 200 mg/liter) as opposed to clinically meaningful concentrations (10 mg/liter or lower), (ii) during ATP- depletion and at acid pH, and (iii) during coincubation with probenecid, gemfibrozil and the preferential multidrug resistance-related protein (MRP) inhibitor MK571. All these conditions were also associated with a marked decrease in ciprofloxacin efflux (half-lives increased from <2 min in controls to up to 10 min). Monensin (a proton ionophore), verapamil, and the preferential P-glycoprotein (P-gp) inhibitor GF120918 had no or only minimal effect, while cyclosporin A, which is not specific for P-gp but also acts on MRP, had an intermediate effect. Short-term uptake studies showed that the influence of the modulators on the apparent drug influx was almost immediate (delay of < or =1 min). Cells made resistant to probenecid and showing a marked overexpression of MRP1 (by Western blot analysis and confocal microscopy) accumulated ciprofloxacin to almost the same extent as did control cells, but efflux was inhibited less by probenecid, gemfibrozil, and MK571. We conclude that ciprofloxacin is subject to constitutive efflux in J774 macrophages through the activity of an MRP-related transporter which is probably distinct from MRP1. We also suggest that the cellular accumulation of ciprofloxacin in wild-type cells is constitutively impaired at therapeutically meaningful concentrations.

Adenosine Triphosphate↗
PubMed1969

Effect of drugs on urate binding to plasma proteins.

The effect of various drugs on urate binding to plasma proteins was investigated in normal subjects. Whereas allopurinol, aspirin, phenylbutazone, probenecid, and sulphinpyrazone all significantly reduced plasma urate concentrations, only aspirin, phenylbutazone, and probenecid significantly impaired urate binding. Colchicine and indomethacin in the doses administered had no significant effect on plasma urate concentrations or binding. In the case of aspirin, urate binding was reduced to 25% of normal, and this effect was quickly abolished after cessation of therapy. Phenylbutazone reduced urate binding to 56% and probenecid to 46% of normal; this impairment was still detected four days after cessation of therapy. Drugs may impair urate binding by competition for plasma protein binding sites, with displacement of bound urate. Impairment of urate binding in vivo by administration of certain drugs may be relevant to the precipitation of acute gouty arthritis, to the formation of gouty tophi, and to the augmentation of uricosuria. Furthermore, the role of drugs must be seriously considered during all studies on urate binding in patients with gout.

Adult↗
PubMed1981

Homovanilic acid in Huntington's disease and Sydenham's chorea.

Homovanilic acid (HVA) was determined in the lumbar CSF of 12 patients with Huntington's disease and 12 with Sydenham's chorea before and after probenecid administration. The means of HVA concentration (basal and after probenecid) were lower in those with Huntington's disease than in controls, and were even lower in a sub-group characterised by increased tone and slowness of voluntary movement. There was no correlation between CSF HVA values and the severity of abnormal movements, nor with length of the illness and age of the patients with Huntington's disease. The mean basal HVA concentration did not differ from controls in those with Sydenham's chorea but the accumulation with probenecid was significantly lower. These results suggest a decrease in cerebral dopamine release in both forms of chorea.

Adult↗
PubMed1983

Cefaclor and cefamandole as alternatives to spectinomycin in the treatment of men with uncomplicated gonorrhoea.

Between 25 December 1981 and 11 March 1982, 400 men with uncomplicated gonococcal urethritis were randomly assigned to one of four treatment regimens: spectinomycin 2 g intramuscularly (group A); cefamandole 1 g intramuscularly after probenecid 1 g orally (group B); cefaclor 3 g orally with probenecid 1 g orally (group C); and cefaclor 3 g orally (group D). The cure rates were 91 of 92 (98.9%) in group A, 68 of 96 (70.8%) in group B, 88 of 92 (95.8%) in group C, and 86 of 96 (89.6%) in group D. Cefaclor at a dose of 3 g given orally with 1 g probenecid appears to be an effective alternative to spectinomycin 2 g in the treatment of gonorrhoea in areas where strains of penicillinase producing Neisseria gonorrhoeae (PPNG) are prevalent.

Cefaclor↗
PubMed1984

Treatment of acute gonococcal urethritis in men with simultaneous infection with Chlamydia trachomatis.

Each of 201 men with symptoms and signs of acute urethritis was randomly assigned to one of two treatment regimens: ampicillin (2g) plus probenecid (1g), or sulphamethoxazole-trimethoprim (SMX-TMP) (sulphamethoxazole 1600 mg plus trimethoprim 320 mg) four tablets twice daily for two days. Before treatment Neisseria gonorrhoeae was isolated from 162 patients, while coexistent Chlamydia trachomatis was recovered from 42 (26%) men. After treatment N gonorrhoeae persisted in 11 (14.3%) of the 77 patients treated with ampicillin and probenecid and in three (3.5%) of the 85 treated with SMX-TMP (p less than 0.05), while C trachomatis persisted in four (16%) of the 25 men treated with SMX-TMP and in all 17 patients treated with ampicillin and probenecid. SMX-TMP was thus more effective than ampicillin in treating acute gonorrhoea in men and in eradicating concurrent C trachomatis infection.

Acute Disease↗
PubMed1985

Two regimens of sultamicillin in treating uncomplicated gonorrhoea.

Sultamicillin is a covalent union of ampicillin and the beta lactamase inhibitor, sulbactam (CP-45,899). Two studies were conducted to assess its efficacy in treating uncomplicated gonorrhoea. In the first study treatment comprised sultamicillin 1.5 g and probenecid 1 g; 124 (89.2%) of 139 patients responded including seven of 11 patients harbouring beta lactamase (penicillinase) producing strains of Neisseria gonorrhoeae (PPNG). In the second study sultamicillin 2.25 g and probenecid 1 g were given; 122 (93.8%) of 130 patients responded. Only two of seven pharyngeal infections resolved, and if pharyngeal infections are excluded the overall cure rate rose to 95.3%. Thirteen of 14 patients infected with PPNG strains were cured by the larger dose. Side effects were mild and transitory. It may be concluded that sultamicillin 2.25 g plus probenecid 1 g is an effective regimen to treat uncomplicated rectal and genital gonorrhoea and is useful for treating infections with PPNG strains. Most beta lactamase resistant antimicrobials must be given parenterally; sultamicillin is given by mouth.

Administration, Oral↗
PubMed1985

Single dose oral amoxycillin 3 g with either 125 mg or 250 mg clavulanic acid to treat uncomplicated anogenital gonorrhoea.

A single supervised oral dose of amoxycillin 3 g combined with clavulanic acid 125 mg as a suspension (Augmentin 3.125G) plus probenecid 1 g, cured 97 of 100 assessable patients who had uncomplicated anogenital gonorrhoea. Thirteen of the 100 patients were infected with penicillinase producing strains of Neisseria gonorrhoeae (PPNG) and 11 (85%) of these patients were cured, including one infected with a PPNG strain that was also resistant to spectinomycin. Another group of 93 assessable patients was treated with ampicillin 3 g plus probenecid 1 g, and only 85 (91%) patients were cured. Of the eight treatment failures in this group, five were found to be infected with PPNG strains. In a second study 144 assessable patients were treated with amoxycillin 3 g combined with clavulanic acid 250 mg, (Augmentin 3.250G) plus probenecid 1 g, and a 97% cure rate was again obtained. Five of seven (71%) patients infected with PPNG strains were cured. Although both Augmentin regimens were effective for treating gonorrhoea caused by PPNG and non-PPNG strains, side effects were noted in more patients treated with 250 mg clavulanic acid (24%) than with 125 mg clavulanic acid (5%). In addition, a similar cure rate was obtained in the three primary sites of infection, the urethra, cervix, and rectum.

Administration, Oral↗
PubMed1994

Kynurenic acid distribution into brain and peripheral tissues of mice.

Kynurenic acid (KYN), an antagonist of excitatory amino acid receptors, is a putative antidote against neuroexcitatory amino acid toxicity. We studied various doses (0.05-3.17 mmol/kg, i.p.) and the effects of probenecid coadministration (0.70 mmol/kg, i.p.) on tissue distribution of KYN in male and female Swiss-Webster mice. After injection of [3H]KYN, samples of brain, heart, liver, kidney, skeletal muscle, and gut were collected at selected times and assayed for KYN by liquid scintillation counting. The substance was absorbed rapidly and distributed into all tissues. Its content (nmol/g, mean +/- SE) at 60 min was 0.26 +/- 0.05, 1.80 +/- 0.05, and 40.4 +/- 8.1 in brain (for 0.05, 0.53, and 3.17 mmol/kg), 1.43 +/- 0.11, 14.3 +/- 3.7, and 212 +/- 32 in heart, 1.16 +/- 0.21, 10.6 +/- 2.6, and 254 +/- 21 in liver, and 7.41 +/- 2.65, 180 +/- 63, and 1899 +/- 254 in kidney. Net accumulation of KYN in brain was much lower than in other tissues. Probenecid increased KYN concentration in brain 2.5-fold. Peak brain:blood concentration ratio occurred between 60 and 180 min, was inversely associated with dose, and was not affected by probenecid. Although brain content was similar, female mice had an earlier peak brain:blood ratio (120 min) than males (180 min) for the 0.05 mmol/kg dose. Our results suggest the presence of a restricted transfer process for KYN with delayed egress from brain.

Animals↗
PubMed1976

Uric acid excretion by the pig kidney.

The handling of uric acid by the pig kidney has been investigated during continuous urate infusion in unrestrained, unanesthetized animals. Urate-to-inulin clearance rates in excess of 1 were found under all experimental conditions, demonstrating only net secretion by the pig kidney. The demonstration of a secretory maximum was precluded owing to a progressive reduction in the GFR associated with high rates of urate infusion. Urate clearance was independent of urine flow rate up to 10 ml/min. The administration of probenecid inhibited urate secretion, but urate-to-inulin clearance ratios below unity were not observed. Pyrazinamide or pyrazinoic acid, at doses which either inhibited secretion or promoted uricosuria in other species, did not alter urate excretion in the pig. Probenecid together with pyrazinamide exerted the same inhibitory effect on urate secretion as probenecid alone. Pyrazinoic acid was reabsorbed at all infusion rates. It is concluded that the pig kidney eliminates uric acid by filtration and secretion only.

Animals↗
PubMed2002

Organic anion transporter 3 (Slc22a8) is a dicarboxylate exchanger indirectly coupled to the Na+ gradient.

Basolateral uptake of organic anions in renal proximal tubule cells is indirectly coupled to the Na(+) gradient through Na(+)-dicarboxylate cotransport and organic anion/dicarboxylate exchange. One member of the organic anion transporter (OAT) family, Oat1, is expressed in the proximal tubule and is an organic anion/dicarboxylate exchanger. However, a second organic anion carrier, Oat3, is also highly expressed in the renal proximal tubule, but its mechanism is unclear. Thus we have assessed Oat3 function in Xenopus laevis oocytes and rat renal cortical slices. Probenecid-sensitive uptake of p-aminohippurate (PAH, an Oat1 and Oat3 substrate) and estrone sulfate (ES, an Oat3 substrate) in rat Oat3-expressing oocytes was significantly trans-stimulated by preloading the oocytes with the dicarboxylate glutarate (GA). GA stimulation of ES transport by oocytes coexpressing rabbit Na(+)-dicarboxylate cotransporter 1 and rat Oat3 was significantly inhibited when the preloading medium contained Li(+) or methylsuccinate (MS) or when Na(+) was absent. All these treatments inhibit the Na(+)-dicarboxylate cotransporter, but not rat Oat3. Li(+), MS, and Na(+) removal had no effect when applied during the ES uptake step, rather than during the GA preloading step. Concentrative ES uptake in rat renal cortical slices was also demonstrated to be probenecid and Na(+) sensitive. Accumulation of ES was stimulated by GA, and this stimulation was completely blocked by probenecid, Li(+), MS, taurocholate, and removal of Na(+). Thus Oat3 functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the Na(+) gradient.

Animals↗
PubMed1978

Organic acid secretory pathway and urinary excretion of prostaglandin E in the dog.

Urinary prostaglandin E (PGE) has been utilized as an index of renal PGE production. Recent studies, however, have suggested that the organic acid secretory pathway is a major determinant of endogenous UPGEV (urinary excretion of PGE). The following experiments were designed to quantitatively test this latter view. In clearance studies the administration of para-aminohippurate (PAH) or probenecid (25 mg/kg) failed to alter endogenous UPGEV although PAH clearance fell with probenecid. Comparison of the excretion patterns of exogenously administered [3H]PGE and [14C]inulin after intra-arterial injection into the dog renal artery (Chinard technique) demonstrated both glomerular filtration and secretion of [3H]PGE. Blockade of the organic acid pathway by probenecid (25 mg/kg) abolished [3H]PGE secretion. Indomethacin (1 mg/kg) did not alter the secretion pattern of [3H]PGE, but decreased endogenous UPGEV by over 80%. Because this low dose of indomethacin did not decrease [3H]PGE secretion, it probably decreased endogenous UPGEV by inhibiting synthesis. Thus, these tracer studies do indeed confirm the suggestion that PGE may be excreted by the organic acid pathway. However, the failure of total endogenous UPGEV to fall after blockade of the organic acid pathway would suggest that the component of UPGEV due to this mechanism is quantitatively insignificant.

Animals↗
PubMed1979

Effects of inhibitors in lumen on PAH and urate transport by isolated renal tubules.

Effects of the presence of unlabeled p-aminohippurate (PAH) or urate, probenecid, and phenol red in the lumen on labeled PAH or urate transport by isolated, perfused snake (Thamnophis spp.) proximal renal tubules were studied. Net secretion of labeled urate and luminal membrane permeability to urate were unaffected by the presence of unlabeled urate (up to 0.1 mM) or probenecid (up to 1.0 mM) in lumen only. The data are compatible with movement of urate from cells to lumen during urate secretion by a simple passive process. Net secretion of labeled PAH was rapidly and reversibly depressed to about 25-35% of control when unlabeled PAH (0.05 mM), phenol red (0.05 mM), or probenecid (0.1 mM) was added to the lumen only. During maximum depression of PAH transport, luminal membrane permeability to PAH was reduced by 60-70%. The data suggest that movement of PAH from cells to lumen down an electrochemical gradient during PAH secretion occurs by a readily inhibited, mediated process.

Animals↗
PubMed1981

Nature of urate transport in isolated rabbit proximal tubules.

Unidirectional fluxes of [14C]-urate from bath to lumen and from lumen to bath were measured in isolated perfused rabbit proximal tubules. The absorption of urate from the perfusate was small in magnitude and relatively insensitive to alteration by luminal probenecid or D-glucose. By contrast, peritubular probenecid inhibited urate secretion from bath to lumen in all three segments. To estimate the facilitated component of urate secretion for each bath concentration of the anion, the passive component of urate influx (probenecid-resistant influx) was subtracted from the total influx of urate. Urate secretion was strongly dependent on concentration of urate in the bath, the relationship being sigmoidal in many S1 and S2 segments. The S0.5 values of 187,251, and 234 X 10(-6) M obtained from Hill plots of mean data from S1, S2, S3 segments, respectively, indicated that the secretory mechanism had a relatively uniform affinity for urate along the proximal tubule. Vmax values for urate secretion were 568,592, and 55 X 10(-15) mol . min-1 . mm-1 for the same segments. Kinetic analysis indicated that axial heterogeneity of urate secretion is probably due to differences in the relative densities of urate transporters of common affinity along the proximal tubule. We suggest that in intact rabbits with low plasma levels urinary urate is the product of glomerular filtration, passive reabsorption, and minimal proximal secretion. With elevation of plasma urate above endogenous levels, S1 and S2 segments secrete urate at an accelerated rate, possibly reflecting action of a transporter with allosteric features.

Animals↗
PubMed1994

Urate transport in brush-border membrane of human kidney.

Mechanisms of urate transport were investigated in human renal brush-border membrane vesicles. The imposition of an outwardly directed Cl- gradient, in voltage-clamp and pH-clamp conditions, stimulated [14C]urate uptake. Organic anions, including pyrazinoate (PZA), probenecid, lactate, ketone bodies, succinate, and alpha-ketoglutarate in their monovalent forms, cis-inhibited [14C]urate uptake. The affinity order was PZA > urate > probenecid > other anions. Vesicle preloading with these anions trans-stimulated urate uptake. These observations demonstrate the presence of a urate/anion exchanger. p-Aminohippurate and OH- were not substrates for this exchanger. In the presence of an inwardly directed K+ gradient and valinomycin (intravesicular positive potential) [14C]urate uptake was stimulated. Voltage-sensitive [14C]urate uptake was cis-inhibited by organic anions in the following affinity order: urate > probenecid > PZA. The differences in affinity orders for the urate exchanger and the urate voltage-sensitive transport suggest different pathways for apical transport. The anion exchanger might be the main mechanism involved in urate tubular reabsorption in humans.

3-Hydroxybutyric Acid↗
PubMed1999

Antioxidant transport modulates peripheral airway reactivity and inflammation during ozone exposure.

We examined the effects of ozone (O(3)) and endogenous antioxidant transport on canine peripheral airway function, central airway function, epithelial integrity, and inflammation. Dogs were either untreated or pretreated with probenecid (an anion-transport inhibitor) and exposed for 6 h to 0.2 parts/million O(3). Peripheral airway resistance (Rpa) and reactivity (DeltaRpa) were monitored in three sublobar locations before and after exposure to either air or O(3). Pulmonary resistance and transepithelial potential difference in trachea and bronchus were also recorded. Bronchoalveolar lavage fluid (BALF) was collected before, during, and after exposure. O(3) increased Rpa and DeltaRpa only in probenecid-treated dogs and in a location-dependent fashion. Pulmonary resistance and potential difference in bronchus increased after O(3) exposure regardless of treatment. O(3) markedly increased BALF neutrophils only in untreated dogs. With the exception of hexanal, O(3) did not alter any BALF constituent examined. Probenecid reduced BALF ascorbate, BALF protein, and plasma urate. We conclude that 1) a 6-h exposure to 0.2 parts/million O(3) represents a subthreshold stimulus in relation to its effects on peripheral airway function in dogs, 2) antioxidant transport contributes to the maintenance of normal airway tone and reactivity under conditions of oxidant stress, 3) O(3)-induced changes in Rpa and DeltaRpa are dependent on location, and 4) peripheral airway hyperreactivity and inflammation reflect independent responses to O(3) exposure. Finally, although anion transport mitigates the effect of O(3) on peripheral airway function, it contributes to the development of airway inflammation and may represent a possible target for anti-inflammatory prevention or therapy.

Airway Resistance↗