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At least 991 records · Page 55Linked to original sources
PubMed1992

Effects of organic acids on stria vascularis ultrastructure and function in the chinchilla.

The purpose of this study was to compare the effects of several organic acids (probenecid, sodium salicylate and penicillin G) on the endocochlear potential (EP) and the ultrastructure of the stria vascularis of the chinchilla with the effects of furosemide on these parameters. Chinchillas received 50 mg/kg i.v. doses of probenecid, sodium salicylate or penicillin G, or 25 mg/kg i.v. furosemide. The EP was monitored continuously before and for 60 min afterwards. The stria vascularis was removed at 10-min intervals from animals and from 10 to 60 min after the injection of these agents. Specimens were then processed for transmission electron microscopy. Only furosemide had an effect on the EP, causing a reversible reduction. The reduction of the EP was accompanied by the appearance of edema in the intercellular spaces of the stria vascularis. No significant edema was found after probenecid, sodium salicylate or penicillin G. This was consistent with the finding that none of these latter three agents affected the endocochlear potential.

Animals↗
PubMed1975

Effect of ECT and imipramine treatment on the concentration of 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in the cerebrospinal fluid of depressed patients.

The influence of probenecid administration on 5HIAA and HVA concentrations in the CSF of depressed patients, was studied before and after treatment with imipramine or ECT. The average increase of the two metabolites in the CSF after probenecid was similar in the untreated depressed patients and in the same patients improved after both imipramine or ECT treatment. The treatment determined a significant increase in the CSF concentration of the acid metabolites also before the probenecid administration.

Adult↗
PubMed1982

Pharmacokinetics of ticarcillin in man.

The excretion of radioactivity has been investigated in 3 healthy volunteers following rapid intravenous administration of 5 g of [35S]-ticarcillin. The radioactive dose was rapidly and completely excreted, since within 4 days 98.5% was recovered, 95% in the urine and 3.5% in faeces. All the urine radioactivity was accounted for as ticarcillin and its penicilloic acid. Plasma and urine samples collected from the volunteers at frequent intervals during the first 6 h of the experiment were assayed for penicillin by an automated chemical method and also for radioactivity. The results obtained by the chemical autoanalyser method were in excellent agreement with the plasma levels of radioactivity. From the data it was possible to calculate the renal clearance of the penicillin, a mean value of 104 ml/min was observed in the 3 volunteers. A further three volunteers were dosed intravenously with a 5 g bolus of non-radiolabelled ticarcillin in a cross-over study with and without predosing with probenecid. Serum samples were analysed by the chemical method for penicillin and the data subjected to pharmacokinetic analysis using a two compartment open model. The results indicate a shift of the distribution equilibrium of ticarcillin from the serum into the peripheral compartment after predosing with probenecid. Furthermore, the mean half-life of ticarcillin in the serum of the three volunteers was significantly increased from 1.3 h to 2.1 h by predosing with probenecid.

Adult↗
PubMed1991

Moment analysis of drug disposition in kidney. V: In vivo transepithelial transport of p-aminohippurate in rat kidney.

A new method that can assess the kinetics of in vivo transepithelial transport in rat kidney has been established. The method is based upon a multiple-indicator dilution experiment and the moment analysis theory. After simultaneous bolus injections of p-aminohippurate (PAH) and inulin into the right renal artery, blood samples were taken from the carotid artery and urine was separately collected from right and left ureters. The characteristic response for the first passage of drugs through the right kidney was evaluated by taking blood circulation into consideration. To determine the mean artery-to-vein transit time and the extraction ratio in the kidney, an intravenous injection was also performed as a reference experiment for deconvolution. The urinary excretion curve corresponding to the first passage was obtained as the difference between both kidneys. The mean artery-to-lumen transit time (mean transepithelial transit time, Tcell) was computed by subtracting the mean urinary transit time of inulin from that of secreted PAH. Since transport across the luminal membrane into the lumen from tubular epithelial cells can influence the cellular residence time of drugs, Tcell and the single-pass mean residence time in epithelial cells (Tcell,sp) can be thought of describing luminal membrane transport. The value of Tcell obtained for 0.1 mM PAH was 22 sec and it was prolonged to 61 sec in the presence of probenecid, suggesting an inhibitory effect on transport across the luminal membrane. On the other hand, antiluminal membrane transport into cells from blood is characterized by the volume of distribution in the kidney (VdPAH). VdPAH was remarkably decreased by treatment with probenecid, indicating an inhibitory effect on antiluminal membrane transport. The effects of probenecid on both sides of epithelial cell membrane transport were first demonstrated in vivo. The present method is useful for the analysis of in vivo transepithelial transport including antiluminal and luminal membrane transport for drugs excreted via tubular secretion.

Animals↗
PubMed1991

Effects of cysteine derivatives of styrene on the transport of p-aminohippurate ion in renal plasma membrane vesicles.

The effects of cysteine conjugates of styrene, e.g. S-1/2-(phenyl-hydroxyethyl) cysteine (PEC) and its N-acetyl derivative (NAPEC) on the transport of p-amino-hippurate (PAH) ion in plasma membranes were studied in vitro using isolated rat renal brush-border membrane (BBM) and basolateral membrane (BLM) vesicles. The uptake of PAH was significantly inhibited by both PEC and NAPEC in both the membrane vesicles, as verified by decrease of the membrane/medium concentration ratio of PAH as the concentration of either PEC or NAPEC in the medium increased. These results show that both PEC and NAPEC are capable of interfering with the accumulation of PAH (a model organic anion for renal tubular transport system) by both energy-independent and energy-dependent carrier-mediated transport processes. The inhibition of PAH uptake in BBM vesicles due to 10 mM PEC or NAPEC was found to be nearly competitive, almost similar to probenecid, whereas in BLM vesicles such inhibition was found to be partially noncompetitive, as verified by the double reciprocal plots. Both PEC and NAPEC showed dose-dependent inhibition of the specific activity of the marker enzyme in each membrane, e.g. gamma-glutamyl transferase in BBM and Na(+)-K(+)-ATPase in BLM vesicles. However, no such inhibition was noticed with probenecid. The in vitro pretreatment with probenecid prevented the inhibition of gamma-glutamyl transferase activity in BBM due to PEC or NAPEC, but such was not the case for the Na(+)-K(+)-ATPase activity in BLM. In conclusion, the data suggest that the transport of cysteine or N-acetylcysteine conjugates of styrene by renal proximal tubular cells across both the membrane vesicles accompanied by the inhibition of the membrane-specific enzymes may lead to cellular dysfunction and consequently to the initial development of their nephrotoxicity.

Animals↗
PubMed1998

The nephrotoxicity and hepatotoxicity of 1,1,2,2-tetrafluoroethyl-L-cysteine in the rat.

Recent studies have shown that tetrafluoroethylene is a renal and hepatic carcinogen in the rat. In this study, we have examined the ability of a single i.p. dose of 1,1,2,2-tetrafluoroethyl-L-cysteine (TFEC), a major metabolite of tetrafluoroethylene, to produce hepatic and renal injury in male and female rats. We have also examined the effect of blocking the renal organic anion transport system with probenecid and of inhibiting the activity of cysteine conjugate beta-lyase with aminooxyacetic acid on the extent of renal injury produced by TFEC. Doses of > or = 12.5 mg/kg TFEC produced renal tubular necrosis to the pars recta of the proximal tubules within 24 h in both male and female rats. This was associated with an increased kidney to body weight ratio and plasma urea at doses of > or = 25 mg/kg. No consistent evidence of liver injury was seen at doses up to 50 mg/kg TFEC in rats of either sex, although occasional vacuolation of hepatocytes and a small dose-related increase in liver to body weight ratio was observed. Prior treatment of female rats with probenecid completely prevented the renal injury produced by either 25 or 50 mg/kg TFEC as judged by plasma urea and histopathology. However, prior treatment of female rats with aminooxyacetic acid afforded no protection against the nephrotoxicity produced by either TFEC or the cysteine conjugate of hexachloro-1,3-butadiene. Thus no major sex difference in nephrotoxicity in the rat was seen with TFEC, while accumulation of TFEC, or its N-acetyl derived metabolite, into renal proximal tubular cells via a probenecid sensitive transport system appears to be a key event in the mechanism of nephrotoxicity. The lack of protection observed with the cysteine conjugate beta-lyase inhibitor, aminooxyacetic acid, may reflect the inability to completely inhibit the mitochondrial form of this enzyme and thereby prevent the formation of the reactive metabolite. Our acute studies provide no insight concerning the liver carcinogenicity of tetrafluoroethylene.

Acetylcysteine↗
PubMed1990

Effect of S-(2-chloroethyl)-DL-cysteine on the transport of p-aminohippurate ion in renal plasma membrane vesicles.

The effects of S-(2-chloroethyl)-DL-cysteine (CEC) (a potent nephrotoxin) on the transport of p-aminohippurate ion (PAH) in renal plasma membrane vesicles isolated from rat renal cortex were studied in vitro. The uptake of PAH was significantly reduced in a dose-dependent manner in both the brush border membrane (BBM) and basolateral membrane (BLM) vesicles. These results demonstrate that CEC is capable of interfering with the accumulation of PAH (a model organic anion for renal tubular transport system) by both energy-independent and energy-dependent carrier-mediated transport processes. Probenecid, a typical inhibitor of the organic anion transport system, showed the highest inhibition of PAH uptake in both the membranes vesicles. These data indirectly suggest that transport by renal tubular cells may result in the accumulation of CEC in renal cellular organelles eventually in toxic concentrations. Thus, CEC showed both dose- and time-dependent inhibition of the activities of gamma-glutamyl transferase (a BBM marker enzyme) and Na+, K(+)-ATPase (a BLM marker enzyme), while no such inhibition was noticed with probenecid. Pretreatment with probenecid prevented the inhibition of the gamma-glutamyl transferase activity due to CEC in BBM, but failed to do so for the Na+,K(+)-ATPase activity in BLM vesicles. Thus, the data suggest that the inhibition of the activities of these membrane-specific enzymes by CEC could lead to the initial development of its nephrotoxicity.

Animals↗
PubMed1981

Renal transtubular transport of mercapturic acid in vivo.

When S-benzyl-N-acetyl-L-[U-14C]cysteine, a mercapturic acid, was administered to rats intravenously, the plasma level of radioactivity decreased very rapidly with a concomitant increase in the renal level of radioactivity. The renal radioactivity reached its maximum within 2 min and then decreased rapidly with concomitant appearance of the radioactive mercapturic acid in the urine. Bilateral ligation of the ureters resulted in only a slight decrease in the rate of disappearance of mercapturic acid from the plasma, while bilateral nephrectomy caused a marked retardation of its clearance from the plasma. Intravenous administration of probenecid, a well known inhibitor of a renal transtubular transport system for organic acids, caused a significant retardation of mercapturate clearance from the plasma in both of the control and ureter-ligated animals. The renal accumulation of this mercapturic acid as well as its excretion into urine was inhibited by probenecid. All these data suggested that a mercapturic acid in the plasma was preferentially taken up by renal tubule cells from the basolateral side of plasma membranes via the probenecid-sensitive transtubular transport system and then excreted rapidly into the lumenal space. This transtubular transport of a mercapturic acid seems to constitute an important process in the hepato-renal cooperation in the mercapturic acid biosynthesis in vivo.

Acetylcysteine↗
PubMed1993

Characterization of p-aminohippurate transport from rat kidney which is expressed after injection of size-selected mRNA into oocytes of Xenopus laevis.

First, the existence of an endogenous p-aminohippurate (PAH) transporter in oocytes of Xenopus laevis was demonstrated. When, however, the oocytes were injected with mRNA from rat kidney cortex, an expressed p-aminohippuric acid (PAH) uptake was seen which differed from the endogenous transporter. Both transport systems are saturated at high PAH concentrations, exhibit trans-stimulation by PAH and are partially inhibited by probenecid. The endogenous transport has a rather low affinity for PAH (Km = 0.57 mM) and is about 50% inhibited by probenecid (one apparent inhibition site with half maximal inhibition at 0.5 mM). The expressed PAH transport has a high affinity for PAH (Km = 60 microM) and can be inhibited 80% by probenecid (two apparent inhibition sites with half maximal inhibitions at 1 microM and 2 mM). Expression experiments with fractionated mRNA revealed that the PAH transport expressed from rat kidney cortex is encoded by an mRNA of 1.8 to 2.5 kb.

Animals↗
PubMed1988

Na+ and H+ gradient-dependent transport of p-aminohippurate in membrane vesicles from dog kidney cortex.

The transport of p-aminohippurate (PAH) was studied in basolateral (BLMV) and brush border membrane vesicles (BBMV) isolated from dog kidney cortex. Imposition of an inwardly directed 100 mN Na+ gradient stimulated the uptake of 50 microM [3H]PAH into BLMV, whereas a pH gradient (pHout = 6.0, pHin = 7.4) only slightly enhanced uptake. The Na+ gradient-dependent uptake of PAH was electroneutral, saturable and sensitive to inhibition by probenecid and several anionic drugs, with (apparent) Km = 0.79 +/- 0.16 mM, Vmax = 0.80 +/- 0.05 nmol/mg protein, 15 sec and Ki for probenecid = 0.08 +/- 0.01 mM. Simultaneous imposition of the pH gradient (outward OH- gradient) and inward Na+ gradient stimulated PAH uptake significantly over that with an Na+ gradient alone. These results are consistent with an Na+ gradient-stimulated PAH/OH- exchange mechanism in the basolateral membrane. In BBMV, PAH uptake could be stimulated by an outwardly directed OH- gradient as well as an inward Na+ gradient. Both gradients could drive PAH transport via a mediated probenecid-sensitive pathway. Na+ gradient-stimulated uptake was electrogenic with a (apparent) Km = 4.93 +/- 0.57 mM, Vmax = 6.71 +/- 0.36 nmol/mg protein, 15 sec and Ki,prob = 0.13 +/- 0.01 mM. The kinetic parameters for PAH/OH- exchange were virtually the same, (apparent) Km = 5.72 +/- 0.49 mM, Vmax = 7.87 +/- 0.33 nmol/mg protein, 15 sec and Ki,prob = 0.16 +/- 0.02 mM. When both the Na+ and pH (outward OH-) gradient were simultaneously imposed an almost twofold stimulation in uptake was observed over that with either an Na+ or pH gradient alone. These results suggested that both gradients stimulate PAH transport in BBMV via the same pathway. However, inhibition experiments with various organic anions showed that the specificities of Na+ and pH gradient-stimulated PAH uptake do not entirely overlap. Thus, our results support a simple transport in BBMV, but it cannot be excluded that two separate pathways are involved.

Aminohippuric Acids↗
PubMed1975

The effect of yohimbine on the turnover of brain catecholamines and serotonin.

Yohimbine moderately increased the depletion of brain dopamine (DA) after alpha-methyl-p-tyrosine (AMT) only when the two drugs were given at the same time; the baseline concentration of brain homovanillic acid (HVA) and its accumulation after probenecid were strongly increased by yohimbine. Yohimbine markedly decreased the concentration of brain noradrenaline (NA), both when given alone and before or at the same time as AMT; when it was given at an increasing interval after AMT, the effect became progressively smaller. The baseline concentration of brain 3-methyoxy-4-hydroxyphenylethyleneglycol sulphate and its accumulation after probenecid were increased by yohimbine; this effect was not as marked as that on HVA and was proportional to the quantity of NA depleted in the Amt method. The accumulation of brain k-hydroxyindoleacetic acid after probenecid was decreased by yohimbine pretreatment.

Animals↗
PubMed1984

Effect of alpha-methyl fluorodopa on dopamine metabolites: importance of conjugation and egress.

The effects of D,L-alpha-monofluoromethyldopa (MFMD), an inhibitor of aromatic L-amino acid decarboxylase, on the metabolism of dopamine (DA) and 5-hydroxytryptamine was investigated using rat brain and cerebrospinal fluid (CSF). Vehicle or MFMD (100 mg/kg) was given p.o. and 16 h later probenecid (200 mg/kg i.p.). CSF was sampled and the rats killed immediately or after 1 h. Vehicle treated rats showed regional differences of percentage conjugation of DA metabolites: 3,4-dihydroxyphenylacetic acid (DOPAC), striatum 10%, rest of brain 45%, CSF 67%; homovanillic acid (HVA), striatum 20%, rest of brain 35%, CSF 53%. These differences and the proportionately greater increases of conjugates than of free acids after probenecid vitiate regional comparisons of DA metabolism if conjugates are not included. MFMD alone decreased neither 5HIAA (except in the striatum) nor the free DA metabolites but decreased both conjugates in CSF and conjugated DOPAC in rest of brain. The inhibitory effects of MFMD on 5HT and DA synthesis were most evident when measured by the accumulation of 5HIAA or total (DOPAC + HVA) after giving probenecid. MFMD may also inhibit amine metabolite egress and the conjugation of DOPAC and HVA.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Effects of oral L-tyrosine administration on CSF tyrosine and homovanillic acid levels in patients with Parkinson's disease.

To determine whether 1-tyrosine administration can enhance dopamine synthesis in humans as it does in rats, we measured levels of tyrosine and the major dopamine metabolite, homovanillic acid, in lumbar spinal fluids of 23 patients with Parkinson's disease before and during ingestion of 100 mg/kg/day of tyrosine. Nine patients took 100 mg/kg/day of probenecid in six divided doses for 24 hours prior to each spinal tap; 14 patients did not receive probenecid. L-tyrosine administration significantly increased CSF tyrosine levels in both groups of patients (p less than .01) and significantly increased homovanillic acid levels in the group of patients pretreated with probenecid (p less than .02). These data indicate that l-tyrosine administration can increase dopamine turnover in patients with disorders in which physicians wish to enhance dopaminergic neurotransmission.

Administration, Oral↗
PubMed1983

Changes of mean arterial pressure of the rat resulting from intracerebroventricular injections of prostacyclin or 6-keto-prostaglandin F1 alpha.

Repeated intracerebroventricular injections of 1 microgram prostacyclin reduce mean arterial pressure of conscious normotensive rats and reverse the elevation of blood pressure of conscious rats resulting from the intraventricular injection of angiotensin II. The reduction of blood pressure of normotensive rats by prostacyclin is enhanced by pretreatment with probenecid, an inhibitor of fatty-acid transport across biological membranes. Although probenecid does not completely inhibit the transport of fatty acids from the brain to the periphery, the greater effectiveness of prostacyclin in probenecid-treated animals suggests that centrally injected prostacyclin need not leak into the periphery to reduce blood pressure. When the dose of prostacyclin is reduced to 100 ng repeated each minute for 10 min, no change of blood pressure of normotensive rats is observed. The failure of the lower dose of prostacyclin to reduce blood pressure may be due to its rapid degradation. Ventricular injections of 6-keto-prostaglandin F1a, a major product of prostacyclin metabolism, causes an increase of blood pressure which may counteract the action of prostacyclin itself.

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Effects of organic acids on the edema of the stria vascularis induced by furosemide.

Furosemide is a loop diuretic which is ototoxic. Investigations have shown the stria vascularis to be the target tissue of this ototoxic drug. The purpose of the present study was to investigate the effects of furosemide on the stria vascularis in chinchillas, in controls and in animals pretreated with the above organic acids. Control animals were injected with 0.5 ml alkalinized saline followed by furosemide IV 30 min later. Experimental animals received probenecid, penicillin or sodium salicylate IV. Thirty minutes later, furosemide was injected in the same dose as in the controls. The basal turn of the stria vascularis was rapidly removed at various times from 10 to 30 min after furosemide administration and processed for transmission electron microscopy. Control animals were found to have reversible edema of the stria vascularis. Experimental animals had variable findings. Those animals pretreated with penicillin had virtually no edema of the stria vascularis at any time. Salicylate and probenecid pretreated animals had significantly less edema from one to 10 min after furosemide injection, but more edema than controls at later times. These findings suggest a discrepancy between ultrastructural pathology and functional status of the cochlea in experimental animals pretreated with probenecid or sodium salicylate followed by furosemide. On the other hand, good structure function correlations were seen in controls and in experimental animals pretreated with penicillin.

Acids↗
PubMed1992

Comparison of three methods of antibiotic prophylaxis in knee arthroplasty.

Prophylactic intravenous cefamandole nafate was administered by the systemic, systemic with probenecid (causing renal tubular blockade of antibiotic excretion), and intravenous regional routes. Bone antibiotic levels were assayed 15 minutes and 12 hours after administration, and hematoma concentrations after 8 hours. Bone concentrations after intravenous regional administration were significantly greater than systemic after 15 minutes, but were not detectable after 12 hours. Probenecid produced inhibitory concentrations in bone after 12 hours and also increased hematoma antibiotic concentrations to three times those achieved by systemic administration. Adequate prophylaxis may be possible with two rather than three doses of cefamandole if probenecid is used.

Cefamandole↗
PubMed1992

Routes for renal transport of methylmercury in mice.

To clarify the routes for renal methylmercury uptake, the effects of ureter ligation and pretreatment of probenecid, an organic anion transport inhibitor, or acivicin, a gamma-glutamyltranspeptidase (gamma-GTP) inhibitor, on renal methylmercury content were investigated in mice. For 120 min after CH3HgCl (5 mumol/kg, i.v.) injection, renal methylmercury content in bilateral ureter-ligated mice was approximately 50% lower than that of sham-operate mice. The glomerular filtration rate was reduced to about 15% of the control by ureter ligation. These results suggest an important role of glomerular filtration in the renal methylmercury uptake. Pretreatment with probenecid (0.5 or 1.0 mmol/kg, i.p.) reduced the renal methylmercury accumulation 30 min after CH3HgCl injection in a dose-dependent manner in both ureter-ligated and sham-operated mice. Urinary methylmercury excretion was not affected by probenecid pretreatment. Renal methylmercury content of ureter-ligated mice was not changed by pretreatment with acivicin (0.5 or 1.0 mmol/kg. i.p.), which was previously reported to decrease the renal methylmercury content in mice. Coadministration of GSH (10 mumol/kg, i.v.) with CH3HgCl increased the renal methylmercury uptake determined 5 min after injection in ureter-ligated mice. These results suggest that at least two transport systems play major roles in renal methylmercury uptake: one is a route from the glomeruli through the brush border membrane which is dependent on the action of gamma-GTP, and the other route is the one using an organic anion transport system through the basolateral membrane.

Animals↗
PubMed2004

Valproic acid uptake by bovine brain microvessel endothelial cells: role of active efflux transport.

The basis for low brain permeability of valproic acid (VPA) appears to be the result of efflux transport at the blood-brain barrier (BBB); however, the identity of the putative efflux transporter has not been investigated. The objective of our studies was to determine whether the multidrug resistance-associated protein (MRP) might be involved in efflux transport of VPA. Brain microvessel endothelial cells (BMEC) were isolated from cow brains and grown to confluence. MRP messenger RNA (mRNA) in BMEC were verified by reverse transcriptase-polymerase chain reaction (RT-PCR). Functional activity was demonstrated using the steady-state retention of calcein and MRP inhibitors, indomethacin (IND) and probenecid (PRB). Probenecid (0.50 mM) and indomethacin (10 microM) produced a 26 and 13% ( P<0.05 ) elevation in steady-state cellular VPA uptake following a 30-min-incubation with tracer 3H-VPA and 30 microM cold VPA. In contrast, at higher concentrations of probenecid (2 mM) and indomethacin (500 microM), an 11 and 31% reduction in VPA uptake was observed. The biphasic pattern of VPA uptake suggested concurrent inhibition of uptake and efflux transporters by the inhibitor with differing sensitivities, i.e. the efflux transporter being more susceptible to inhibition than the influx transporter. Similar results were obtained in the MRP overexpressing cell line A549. Overall, the results suggest that MRP(s) is(are) involved in the efflux transport of VPA, but do not preclude the possible contribution(s) of other organic anion transporters. The findings also adds to the growing evidence that up-regulation of active drug efflux transporters at the BBB may contribute to the development of drug resistance to antiepileptic drug therapy.

Adenocarcinoma↗