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PubMed1990

[Mechanism of action of the diuretic effect of muzolimine].

Muzolimine is a diuretic which has been proposed in the treatment of hypertension. Muzolimine shared both the high ceiling effect of loop diuretics and the long duration of action of thiazides but has a chemical structure different from those of other loop diuretics. It may act as a prodrug and an active metabolite present in the urine may inhibit NaCl reabsorption in the Henle's loop. We studied the effect of urines of piretanide and muzolimine treated rats on Na+K+Cl- cotransport in renal cells in culture (MDCK). In the presence of ouabain (0.5 mM), the Na+K+Cl- cotransport measured by 86Rb influx, represented 92 p.100 of the total 86Rb influx (6.16 +/- 1.12 nmol 86Rb/min/mg prot, n = 10). Both diuretics were administered i.v. to rats where they induced marked diuresis. Excreted urine (dilution to 1/100) was tested for cotransport inhibition. After piretanide (27 mumol/kg) the urine inhibited the Na+K+Cl- cotransport in MDCK cells (72% and 41% inhibition at the 15th and 45th minutes after diuretic injection). After muzolimine (50 mumol/kg), urines also inhibited Na+K+Cl- cotransport but the effect was slower in onset and more prolonged (42% and 49% inhibition at the 15th and 60th min). Diuretic effects in vivo and Na+K+Cl- cotransport inhibition in vitro by the urine developed parallel for both diuretics. Probenecid (100 mumol/kg) suppressed simultaneously the diuretic effect of muzolimine and the Na+K+Cl- cotransport inhibition by the urine of muzolimine treated rats. Our results suggest that muzolimine acts as a prodrug. Its active metabolite is secreted into the tubular lumen through a probenecid sensitive pathway and inhibits, like other loop diuretics, Na+K+Cl- cotransport.

Animals↗
PubMed1990

In vivo evidence for carrier-mediated uptake of beta-lactam antibiotics through organic anion transport systems in rat kidney and liver.

The transport mechanisms of beta-lactam antibiotics in the rat kidney and liver were studied with an in vivo tissue-sampling single-injection technique using [3H]benzylpenicillin [( 3H]PCG) as a substrate. Concentration-dependent uptake of [3H]PCG was observed in the kidney, and the in vivo kinetic parameters were estimated as follows: the maximum uptake rate (Jmax) was 6.88 mumol/min/g of kidney, MIchaelis constant (Kt) was 1.39 mM and nonsaturable first-order rate constant (kd) was 0.414 ml/min/g of kidney. The uptake of [3H]PCG was inhibited by organic anions but not by organic cations. Several beta-lactam antibiotics also reduced the uptake of [3H]PCG. Furthermore, the organic anion, probenecid, and beta-lactam antibiotic, cefpiramide, showed a dose-dependent inhibitory effect. These results suggest participation of an organic anion transport system in uptake of beta-lactam antibiotics across the renal plasma membrane. Saturable uptake of [3H]PCG was also observed in the liver and Jmax, Kt and Kd were estimated to be 3.62 mumol/min/g of liver, 3.59 mM and 0.223 ml/min/g of liver, respectively. The in vivo influx rate calculated from Jmax/Kt in the liver was 1.01 ml/min/g of liver and was close to the in vitro value, 1.54 ml/min/g of liver, estimated previously from isolated hepatocytes. Although dipeptides and organic cations showed no effect on the hepatic uptake of [3H]PCG, probenecid significantly reduced its uptake. Several beta-lactam antibiotics also reduced the uptake of [3H]PCG by the liver. These features of the hepatic uptake of beta-lactam antibiotics through an organic anion transport system are in agreement with the previous results obtained in isolated hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1975

Renal mechanisms for the excretion of nicotinic acid.

Nicotinic acid, an essential endogenous organic acid, was studied in free-flow clearance experiments in the dog at plasma concentrations ranging from 1.2 to 600 mug/ml. At all concentrations, net reabsorption was observed. At concentrations of 1.2 mug/ml, the clearance of nicotinic acid as compared to the clearance of insulin was approximately 0.50. As nicotinic acid plasma concentrations were increased to 90 mug/ml, the clearance ratio declined to 0.22. The clearance ratio then steadily increased to 0.75 as plasma concentrations reached 600 mug/ml. Plasma levels of nicotinic acid in excess of 600 mug/ml resulted in renal toxicity as indicated by a marked decrease in the glomerular filtration rate. The decline in the clearance ratio in the presence of 90 mug/ml of nicotinic acid suggested saturation of a secretory system and hence cyanine 863 and probenecid were used to observe their effects on the clearance ratio. The base transport inhibitor was without effect; probenecid decreased the clearance. Alkalinization of the urine had no noticeable effect on nicotinic acid clearance. Protein binding did not occur. The data indicate two important points. First, nicotinic acid is secreted to a limited degree by the organic anion secretory system and is simultaneously reabsorbed. Second, a homeostatic mechanism for conservation of nicotinic acid at low plasma levels does not seem to exist.

Animals↗
PubMed1990

Organic anion secretion by winter flounder renal proximal tubule primary monolayer cultures.

Recent models of para-aminohippuric acid (PAH) transport by renal proximal tubule have been deduced from isolated membrane vesicles and stopped flow microperfusion. The flounder proximal tubule primary monlayer cultures mounted in Ussing chambers have provided a means to examine the relationship of these models to transepithelial transport. Unidirectional transepithelial 3H-PAH fluxes were determined in 12-day-old monolayers on floating collagen gels under continuously short-circuited conditions. The kinetic values of PAH secretory flux were complex. Over the range of 0.6 microM to 1.5 mM the K1/2 was 0.4 mM and Vmax was 80 nmol/cm2/h. Reabsorptive flux did not saturate. 1 mM probenecid inhibited 95% of the secretory flux (0.07 +/- 0.18 compared with control of 1.38 +/- 0.34 nmol/cm2/h at 10 microM PAH) and had no significant effect on reabsorptive flux (probenecid, 0.07 +/- 0.04; control, 0.05 +/- 0.01 nmol/cm2/h). 0.1 mM 4-acetamido-4'-isothiocyanalostilbene-2,2'-diasulfonic acid and 1 mM benzoylpropionic acid also significantly inhibited secretory flux (95 and 78%, respectively). These inhibitors appeared to be specific in that no effects on transepithelial potential difference, resistance or phlorizin-sensitive current were seen. Removal of Na during flux measurement reduced net PAH secretion to zero, and 1 mM ouabain reduced PAH secretory flux to 10% of control within 90 min with no effect on reabsorptive (leak) flux. Clamping transepithelial voltage to +/- 10 mV had no significant effect on PAH fluxes. Addition of glutarate to flounder saline significantly inhibited PAH secretory flux starting at 0.1 mM and caused 90% inhibition at 1 mM; no stimulation of transport was noted at any glutarate concentration.

Animals↗
PubMedDate not supplied

In vivo and in vitro renal metabolism and excretion of benzoic acid by a marine teleost, the southern flounder.

In mammals, benzoic acid is primarily metabolized to its glycine conjugate, hippuric acid, which is readily excreted via the renal organic anion transport system. Teleost fish have not been shown to make glycine conjugates of carboxylic acids. Therefore, metabolism, excretion, and renal transport of benzoic acid were examined in the southern flounder, Paralichthys lethostigma. Excretion of injected [14C]benzoic acid was slow (10% of the administrated dose/day) and followed zero order kinetics. More than 95% of the excreted label was a single metabolite which was shown by hydrolysis and TLC to be benzoyltaurine. Isolated renal tubules and both hepatic and renal mitochondria produced benzoyltaurine in vitro. Excretion of benzoic acid and benzoyltaurine were not limited by plasma binding (less than 5% bound). To examine whether the slow excretion reflected renal transport, the transport of 100 microM benzoic acid, benzoyltaurine, and hippuric acid were determined in isolated renal tubules. All three compounds were accumulated via a probenecid- and cyanide-sensitive mechanism. Probenecid-sensitive uptake at 60 min of hippuric acid (436 nmol/mg) was greater than that of benzoyltaurine (164 nmol/mg) and both exceeded uptake of benzoic acid (63 nmol/mg). The same pattern was seen at 10 microM, except that tissue:medium ratios were even greater, indicating at least partial saturation of transport at 100 microM. Thus, the slow excretion of benzoic acid by these flounder was due to a combination of factors, including slow metabolism of benzoic acid to benzoyltaurine, saturation of the transport of benzoyltaurine, and low affinity of secretory transport for benzoic acid and benzoyltaurine, relative to hippuric acid, the mammalian metabolite.

Animals↗
PubMedDate not supplied

Kinetic studies on the competition between famotidine and cimetidine in rats. Evidence of multiple renal secretory systems for organic cations.

The H2-receptor antagonists famotidine and cimetidine are both basic drugs that are predominantly eliminated by the kidneys. Cimetidine has been shown to inhibit the renal secretion of tetraethyl-ammonium bromide (TEAB) but not p-aminohippuric acid (PAH), suggesting that cimetidine is secreted by an organic cation transport system [Weiner and Roth: J. Pharmacol. Exp. Ther. 216: 516 (1981)]. The present study shows that famotidine behaves like cimetidine in that it also inhibits TEAB but not PAH excretion. Where a high concentration of cimetidine in plasma has an inhibitory effect on the renal excretion of famotidine, the reverse is not true, i.e. high plasma levels of famotidine have no effect on the excretion of cimetidine. Further evidence that additional transport systems are involved in the renal tubular secretion of cimetidine is as follows. Quinine, a potent competitor of the organic cation transport system, inhibits the secretory component of famotidine renal clearance but not that of cimetidine. Probenecid, a classic competitor for the organic anion transport system, inhibits the renal excretion of cimetidine but not famotidine. However, the effect of probenecid is minor and not sufficient to account for other components of cimetidine secretion not affected by famotidine and quinine.

Animals↗
PubMedDate not supplied

Differential renal handling of angiotensin-converting enzyme inhibitors enalaprilat and lisinopril in rats.

Enalaprilat, the active metabolite of enalapril, and its lysine analogue lisinopril are potent nonsulfhydryl angiotensin-converting enzyme inhibitors. Earlier studies from our laboratories demonstrated that neither drug is significantly metabolized, and both are almost exclusively eliminated by renal excretion. This report compares the renal excretory mechanisms for these structurally related compounds in the rat. After an iv, 1-mg/kg dose, ratios of renal clearance (CLR) of unbound drug to glomerular filtration rate (GFR) for enalaprilat and lisinopril were 2.72 +/- 0.70 and 1.01 +/- 0.18, respectively, suggesting that enalaprilat, but not lisinopril, was actively secreted by the kidneys. Treatment with probenecid and p-aminohippuric acid, potent competitive inhibitors for the renal anionic transport system, caused a profound decrease in the renal clearance of enalaprilat to the level of GFR. The CLR/fu.GFR, where fu is the unbound fraction, became 1.10 +/- 0.09 and 1.25 +/- 0.25, respectively. These results and the fact that quinine, a potent inhibitor for the cationic transport system, had little effect on the renal clearance of enalaprilat indicated that enalaprilat is secreted by the organic anion transport system. On the other hand, probenecid, p-aminohippuric acid, and quinine had no effect on the renal clearance of lisinopril, suggesting that lisinopril is eliminated exclusively by glomerular filtration.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

Renal handling of 5-nitrofuran nephrotoxins in the rat.

Formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl)-hydrazide (FNT) and 3-hydroxymethyl-1-([3-(5-nitro-2-furyl)-allydidene]amino)hydantoin (HMN) were investigated to determine whether differences in the renal handling of these two chemicals might provide evidence to explain their different patterns of toxicity and carcinogenicity. The isolated perfused rat kidney and whole animal were used. In the isolated perfused rat kidney, both FNT and HMN had similar half-lives (t1/2) but the urinary excretion and renal clearance of HMN (2.1 +/- 0.4 greater than those of FNT (0.2 +/- 0.1 nmol/min and 0.06 +/- 0.01 ml/min, respectively). Probenecid increased the t1/2 and decreased the metabolic clearance of HMN but did not have any effect on FNT t1/2 or clearance. These differences in excretion of FNT and HMN could not be explained on the basis of protein binding. The total clearances of FNT and HMN were similar and significantly higher than that of the 5-nitrofuran bladder carcinogen ANFT. In the whole animal, the urinary excretion of HMN was about 10-fold greater than that of FNT. The t1/2 of both FNT and HMN was less than 5 min in the whole animal. Probenecid decreased the urinary excretion of HMN from 9.7 +/- 1.4% to 4.4 +/- 1.0% (p less than 0.05). Compared with HMN, FNT has less urinary excretion but a similar elimination t1/2, suggesting a greater nonrenal clearance. HMN but not FNT has tubular excretion. Thus, alterations in substituents of 5-nitrofurans markedly alter their renal handling and may partially explain their diverse toxic effects.

Animals↗
PubMed1979

Penicillin levels in blood and CSF achieved by treatment of syphilis.

Treponemicidal levels of penicillin in the CSF were not obtained following intramuscular (IM) injections of 600,000 IU of penicillin G procaine along with 2% aluminum monostearate (PAM). Treponemicidal levels of penicillin in the CSF were achieved in 31 patients by probenecid, 500 mg/6 hr by mouth, with penicillin G, 500,000 IU by IM injection, and by probenecid every six hours by mouth and IM injections of penicillin G procaine once a day in two of three patients following injections of 600,000 IU, in four of five following 1.2 million IU, and in three (now all nine) following 2.4 million IU.

Administration, Oral↗
PubMed1987

Permeability of the blood-retinal barrier to carboxyfluorescein in eyes with rhegmatogenous retinal detachment.

Outward and inward permeability of carboxyfluorescein across the blood-retinal barrier were measured fluorophotometrically in seven cynomolgus monkey eyes with experimental rhegmatogenous retinal detachment. Probenecid was used to inhibit outward transport of carboxyfluorescein. The outward permeability was 1.98 +/- 0.31 microliter/min in eyes with retinal detachment and 0.84 +/- 0.15 microliter/min in control eyes with vitrectomy alone (P less than 0.01). The inward permeability, determined separately following intravenous injection, was significantly lower than the outward permeability: 0.14 +/- 0.02 microliter/min for eyes with retinal detachment and 0.04 +/- 0.01 microliter/min for control eyes. Since the outward permeability minus the inward permeability in the presence of probenecid represents that fraction of tracer moving due to fluid flow, it may be concluded that outward flow of fluid across the blood-retinal barrier is a substantial contributor to carboxyfluorescein loss from the vitreous cavity following intravitreal injection.

Animals↗
PubMed1987

Diabetic renal hypouricemia.

In diabetes, the serum uric acid level is low due to increased urate clearance; however, its mechanism remains unknown. We examined seven maturity-onset diabetic patients with rarely reported hypouricemia due to renal tubular abnormality to better understand the renal handling of urate by the diabetic kidney. The results of studies indicate that the increase in urate clearance was entirely accounted for by increased pyrazinamide-suppressible urate clearance. The maximal uricosuric response to probenecid administration was exaggerated. The effects of drugs on urate clearance were similar to those we have previously reported in the syndrome of inappropriate secretion of antidiuretic hormone. In four patients, the family survey did not reveal anyone with hypouricemia. These observations suggest that hypouricemia due to hyperuricosuria, which responds markedly to pyrazinamide and probenecid, is actually an indicator of renal tubular abnormality in diabetics.

Adult↗
PubMed1986

Clearance of furosemide by the gastrointestinal tract.

Approximately 45% of i.v. administered furosemide is eliminated by nonrenal clearance mechanisms. Indirect evidence suggests this might represent intestinal secretion. Therefore, we examined whether the intestinal tract serves as a drug-eliminating organ in man. Intestinal perfusion studies were performed in six healthy volunteers during i.v. furosemide administration (mean serum concentration, 3.74 +/- 0.64 microgram/ml). Subjects were intubated with a multilumen tube which allowed examination of transmucosal water, solute and furosemide movement at separate levels of the gastrointestinal tract. A poorly absorbable electrolyte-mannitol solution was infused in the jejunum (15 ml/min), with polyethylene glycol as a nonabsorbable marker. Furosemide elimination occurred at an equally low rate in all areas of the intestinal tract. Furosemide clearance for the total gastrointestinal tract was 2.1 +/- 0.4 ml/min (mean +/- S.E.M.) compared to a renal clearance of 93.1 +/- 4.6 ml/min. Thus, gastrointestinal elimination amounted to only 2% of renal elimination. The luminal concentration of furosemide in the intestinal tract did not exceed a mean of 0.5 microgram/ml. When the experiments were repeated after administration of probenecid, gut clearance was unchanged but renal clearance was reduced by 70%. In the ileum, furosemide enhanced bicarbonate secretion and induced chloride absorption. We conclude that the intestinal tract contributes only minimally to furosemide elimination in man. From concentration gradients between lumen and plasma and from the fact that probenecid had no effect on elimination rate, it appears likely that active secretion into the intestinal lumen does not occur and that all furosemide appearance in the gut results from passive diffusion.

Adolescent↗
PubMed1985

Renal tubular excretory transport of oxalate in the chicken.

By use of the Sperber in vivo chicken preparation, infusion of radiolabeled oxalic acid ([14C]oxalate) into the renal portal circulation indicated net excretory transfer of unchanged oxalate. At infusion rates of 0.1 to 100 nmol/min, approximately 26% of the oxalate reaching the kidney was excreted directly into the urine. The excretory transport of oxalate was not altered by infusion of probenecid or terephthalic acid, at rates that blocked completely the excretory transport of simultaneously infused p-aminohippuric acid. Because probenecid and terephthalic acid are also known to inhibit uric acid excretory transport in the chicken kidney, these findings suggest that the transport system for oxalate in the chicken kidney is separate from those handling p-aminohippuric acid and uric acid. The excretory transport of oxalate was decreased by the infusion of alpha-ketoglutaric acid, suggesting that oxalate competes at least in part with other endogenous dicarboxylic acids for uptake at the peritubular membrane.

Animals↗
PubMed1985

Structure-nephrotoxicity relationships of S-(2-chloroethyl)-DL-cysteine and analogs: role for an episulfonium ion.

1,2-Dichloroethane produces kidney damage, but the mechanism is unclear. Cysteine conjugates, which could arise from S-(2-chloroethyl)glutathione or S-(2-chloroethyl)cysteine have been identified. In this study, rats given S-(2-chloroethyl)-DL-cysteine (100 mg/kg i.p.) showed significant increases in blood urea nitrogen and urine glucose concentrations. Histopathological examination of kidneys, 36 hr after treatment showed acute proximal tubular nephrosis and punctuate glomerular necrosis. No hepatic lesions were seen and serum glutamate-pyruvate transaminase activities were only elevated slightly. The extent of S-(2-chloroethyl)-DL-cysteine renal toxicity was dose- and time-dependent. Equimolar doses of analogs of S-(2-chloroethyl)-DL-cysteine, S-ethyl-L-cysteine, S-(2-hydroxyethyl)-N-acetyl-DL-cysteine, S-(2-hydroxyethyl)-DL-cysteine, or S-(3-chloropropyl)-DL-cysteine, failed to produce nephrotoxicity; rats given L-cysteine (100 mg/kg i.p.), S-ethyl-L-cysteine (100 mg/kg i.p.) or probenecid (60 mg/kg i.p.) 30 min before receiving S-(2-chloroethyl)-DL-cysteine had significant reductions of the S-(2-chloroethyl)-DL-cysteine-induced blood urea nitrogen and urine glucose elevations. These results show that S-(2-chloroethyl)-DL-cysteine is a potent, selective nephrotoxin that may be responsible for the renal damage associated with 1,2-dichloroethane. The formation of an episulfonium ion plays an important role in S-(2-chloroethyl)-DL-cysteine-induced nephrotoxicity. The protection against renal damage provided by S-ethyl-L-cysteine or probenecid may involve competition with S-(2-chloroethyl)-DL-cysteine for cellular or transport binding sites.

Acute Kidney Injury↗
PubMed1985

Studies on the mechanism for renal elimination of N-acetylphenylalanine: its pathophysiologic significance in phenylketonuria.

To elucidate the mechanism and biologic significance of urinary occurrence of N-acetylphenylalanine in phenylketonuria, the metabolic fate of N-acetylphenylalanine was studied in rats. In vivo and in vitro analysis revealed that N-acetyl-14C(ul)-phenylalanine bound to plasma albumin with an association constant of 8.52 X 10(3) M-1 and that the number of binding sites was 0.98 per mole albumin. Intravenously administered N-acetylphenylalanine was rapidly extracted from the circulation predominantly by the kidney and excreted into urine. Plasma clearance of the injected ligand was markedly decreased by bilateral nephrectomy but not by bilateral ureter ligation. Probenecid, a potent inhibitor of the renal excretory system for organic anions, such as hippuric acid, sharply decreased the rate of disappearance from the circulation, renal accumulation, and urinary secretion of intravenously administered N-acetylphenylalanine. These results indicate that intravenously administered N-acetylphenylalanine undergoes renal peritubular transport via a probenecid-sensitive excretory system for organic anions. This renal transtubular excretory mechanism may possibly operate in elimination of N-acetylphenylalanine, a hazardous amphipathic metabolite of phenylalanine, from plasma into urine in phenylketonuric patients.

Animals↗
PubMed1985

[Formation of volatile carcinogenic N-nitroso compounds from drugs under simulated human gastric conditions].

41 commercial drugs approved for peroral application in the GDR, whose active agents contain N,N-dialkylamino groups in their chemical structures, have been investigated under simulated conditions of the human stomach. With the drugs containing aminophenazone, amitriptyline, doxycycline and oxytetracycline as active agents N-nitrosodimethylamine is formed as a result of nitrosation reactions. With the drugs containing clomiphene++, disulfiram, probenecid and a diethylamine-containing liquid hypnoticum, there occurred N-nitrosodiethylamine. In no case N-nitrosodi-n-propylamine or N-nitrosopiperidine were detectable. The isolated active agents amitriptyline, clomiphene++ and probenecid themselves proved not to be nitrosatable. The positive findings with these drugs were caused by not yet identified nitrosatable contaminants of these drugs. The quantitative determination of volatile N-nitroso compounds was done upon steam distillation by means of gas chromatograph and chemiluminescence detector.

Aminopyrine↗
PubMedDate not supplied

Effect of pentobarbital anesthesia on serotonin metabolism in hypoxic rat brain.

Two hours of pentobarbital anesthesia resulted in marked elevation of serotonin (5-HT) level and decreased accumulation of 5-hydroxyindolacetic acid (5-HIAA) after probenecid, in specific parts of rat brain. In hypoxia, either no change (cortex, hypothalamus) or an increase (striatum, pons with medulla) in 5-HT content was observed. Concomitantly, the decrease of 5-HIAA level and its accumulation after transport inhibition occured. Pentobarbital pretreatment of hypoxic rats resulted in further diminution of 5-HT degradation after probenecid, having synergistic character in pons with medulla, which points to the specific sensitivity of serotonergic system in the latter area. Hypoxia-induced decrease of 5-HIAA level was prevented by pentobarbital pretreatment. The possible participation of 5-HIAA efflux inhibition in this phenomenon is discussed.

Anesthesia↗
PubMed1974

Oral amoxicillin in acute uncomplicated gonorrhea.

Of 53 patients with acute uncomplicated gonorrhea treated with amoxicillin 2 g and probenecid 1 g orally as a single administration, six failed to return for follow-up examination, 10 developed postgonococcal urethritis and one was a treatment failure. The remainder achieved symptomatic cure in an average of 2.3 days. Adverse drug effects were infrequent, mild and transient. We conclude that this dose of amoxicillin and probenecid is a safe and effective treatment regimen.

Acute Disease↗