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PubMed2002

Characterization of methotrexate transport and its drug interactions with human organic anion transporters.

Life-threatening drug interactions are known to occur between methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs), probenecid, and penicillin G. The purpose of this study was to characterize methotrexate transport, as well as to determine the site and the mechanism of drug interactions in the proximal tubule. Mouse proximal tubule cells stably expressing basolateral human organic anion transporters (hOAT1 and hOAT3) and apical hOAT (hOAT4) were established. The K(m) values for hOAT1-, hOAT3-, and hOAT4-mediated methotrexate uptake were 553.8 microM, 21.1 microM, and 17.8 microM, respectively. NSAIDs (salicylate, ibuprofen, ketoprofen, phenylbutazone, piroxicam, and indomethacin), probenecid, and penicillin G dose dependently inhibited methotrexate uptake mediated by hOAT1, hOAT3, and hOAT4. Kinetic analysis of inhibitory effects of these drugs on hOAT3-mediated methotrexate uptake revealed that these inhibitions were competitive. The K(i) values for the effects of salicylate, phenylbutazone, indomethacin, and probenecid on hOAT3-mediated methotrexate uptake were comparable with therapeutically relevant plasma concentrations of unbound drugs. In addition, in the presence of human serum albumin, the K(i) values were comparable with therapeutically relevant total plasma concentrations of drugs. In conclusion, these results suggest that methotrexate is taken up via hOAT3 and hOAT1 at the basolateral side of the proximal tubule and effluxed or taken up at the apical side via hOAT4. In addition, hOAT1, hOAT3, and hOAT4 are the sites of drug interactions between methotrexate and NSAIDs, probenecid, and penicillin G. Furthermore, it was predicted that hOAT3 is the site of drug interactions between methotrexate and salicylate, phenylbutazone, indomethacin, and probenecid in vivo.

Animals↗
PubMed1996

ANP-stimulated cGMP egression in renal principal cells: abrogation of polarity by SV40 large T.

Egression of atrial natriuretic peptide (ANP)-stimulated guanosine 3', 5'-cyclic monophosphate (cGMP) was compared with that of isoproterenol-stimulated adenosine 3', 5'-cyclic monophosphate (cAMP) in a rabbit collecting duct cell line transformed with a temperature-sensitive strain of simian virus 40 (SV40). At 39.5 degrees C (inactivated large T), cells exhibit major features of principal cells, whereas at 33 degrees C (functional large T) they lose most of their specific properties. When cells were grown on plastic at 39.5 degrees C, both cyclic nucleotides were predominantly released extracellularly via probenecid-sensitive carriers. Probenecid (3mM) reduced the ratios of extracellular cGMP and cAMP by 84 and 70%, respectively. The amount of extracellular cGMP or cAMP ws linearly correlated with the time integral of the intracellular cyclic nucleotide, suggesting first-order kinetics. The apparent first-order rate constant (k) was sixfold greater for cGMP (0.139 +/- 0.037 min-1, n = 3 experiments) than for cAMP (0.022 +/- 0.003(-1), n = 3 experiments). 3-Isobutyl-1-methylxanthine markedly inhibited extrusion of cGMP (k = 0.022 +/- 0.003 min-1), whereas that of cAMP was unchanged. When cells were grown on filters at 39.5 degrees C, both nucleotides were predominantly released in the apical medium but with a greater polarity for cGMP (83 +/- 4%, n = 6 experiments) than for cAMP (60 +/- 6%, n = 3 experiments) and a prevailing apical localization of the probenecid-sensitive carrier. Activation of SV40 large T at 33 degrees C did not alter cyclic nucleotide transport characteristics but abolished the polarity of probenecid-sensitive cyclic nucleotide extrusion. These results suggest a physiological role for luminal cGMP in the rabbit collecting duct and a specific effect of large T on the probenecid-sensitive carrier polarity.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Acid metabolites and precursor amino acids of 5-hydroxytryptamine and dopamine in affective and other psychiatric disorders.

Levels of various compounds related to monoamines were assessed in 96 patients with a variety of depressive and nondepressive syndromes. The diagnostic categories were composed retrospectively after examination of International Classification of Diseases (ICD) classifications and all available data in medical reports. All patients underwent the 8-hour probenecid test. Administration of probenecid was partly intravenous (1 g) and partly oral (4 g). In all patients, the cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and probenecid were estimated, while in about half of the patients tryptophan and tyrosine were determined in CSF and serum. When the group is taken as a whole, significant positive correlations are found between the CSF levels of 5-HIAA, HVA and probenecid, between the CSF levels of tryptophan and tyrosine, and between tyrosine levels in serum and CSF. A negative correlation is found between CSF probenecid and serum tryptophan. The group of patients was divided in several ways into various subgroups. Analysis of covariance of clinical and biochemical data indicates no significant biochemical differences between any of the subgroups. This retrospective study lacks supportive evidence that any of the clinical syndromes, including the depressive syndromes, is characterized by specific deficiencies of monoamine neurotransmission.

Adjustment Disorders↗
PubMed1976

Homovanillic acid transport by the spinal cord.

Spinal subarachnoid perfusions of rhesus monkeys were performed to study spinal transport of homovanillic acid in control and probenecid-treated animals. Homovanillic acid enters capillaries within spinal tissue throughout the spinal cord. The mean capillary exchange half-time for homovanillic acid was 19.2+/-2.8 minutes; probenecid did not affect this value significantly. Despite its polar nature, homovanillic acid crosses cell boundaries easily and equilibrates in a distribution volume (55 percent) approaching the total water space. The spinal cord clears homovanillic acid from 21+/-4 mul per minute of cerebrospinal fluid. The rate of clearance after probenecid administration was not significantly different. The apparent diffusion coefficient in tissue of homovanillic acid approximated the diffusion coefficient in water (8.0 X 10(-6) cm2 per second). The data show that homovanillic acid is transported by capillaries throughout spinal tissue by a mechanism largely insensitive to inhibition by probenecid. Lumbar cerebrospinal fluid concentrations of homovanillic acid even after probenecid administration therefore reflect only part of the total dopamine metabolism.

Animals↗
PubMed1995

Sex-dependent and independent renal excretion of nilvadipine metabolites in rat: evidence for a sex-dependent active secretion in kidney.

1. To clarify the mechanism of sex-dependent and independent kidney secretion of major nilvadipine metabolites (3, 7) in rat, renal clearance corrected for protein binding and glomerular filtration rate (GFR) was measured in both sexes. The effect of probenecid, an inhibitor of organic anion transport, on these measurements was also investigated. 2. Clear sex-dependent active secretion was observed in the renal excretion of 3 (3-carboxylic acid pyridine derivative). In the female rat, 3, clearance was approximately 32-fold greater than GFR and was markedly decreased by probenecid. Conversely, in the male rat, renal clearance of 3 was only a fraction of GFR and was unaffected by probenecid. 3. Sex-independent active secretion was observed in the renal excretion of 7 (5-carboxylic acid pyridine derivative). In both sexes of rat 7 clearance was about 22-fold greater than GFR and was markedly reduced by probenecid. 4. A clear presence of sex-dependent and independent active secretion mechanisms in the kidney has been demonstrated in rat. The female rat is able to eliminate 3 and 7 in urine by an active secretion mechanism that is inhibited by probenecid. In the male rat, a transport mechanism for 7 is present, but either lacks or is apparently inactive for 3.

Animals↗
PubMed1989

Single-dose efficacy of ofloxacin in uncomplicated gonorrhea.

Two multicenter trials compared single-dose oral therapy with 400 mg of ofloxacin or 3 g of amoxicillin plus 1 g of probenecid in the treatment of uncomplicated gonorrhea in 160 men and 102 women. Patients with a known diagnosis of Chlamydia trachomatis infection were excluded. All pretreatment isolates of Neisseria gonorrhoeae were susceptible to ofloxacin (minimal inhibitory concentration less than or equal to 2 micrograms/ml), whereas roughly 50 percent exhibited intermediate susceptibility to ampicillin (minimal inhibitory concentration, 0.125 to 2.0 micrograms/ml). Post-treatment culture results showed that ofloxacin had eradicated N. gonorrhoeae in 97.5 percent (41 men) of 42 men and all 28 women evaluated. Amoxicillin-probenecid achieved microbiologic cures in 92.7 percent (51 men) of 55 men and 92.6 percent (25 women) of 27 women evaluated. Clinical cure rates among initially symptomatic patients were 84.6 percent (33 men) of 39 men and 81.8 percent (nine women) of 11 women with ofloxacin and 83.0 percent (44 men) of 53 men and 66.7 percent (10 women) of 15 women with amoxicillin-probenecid. No drug-related adverse effects were noted in ofloxacin-treated patients. One patient each in the amoxicillin-probenecid group reported nausea, diarrhea, and vaginitis. These results demonstrate that single-dose ofloxacin is as effective as amoxicillin-probenecid in eradicating N. gonorrhoeae and relieving clinical signs and symptoms of gonococcal infections in both men and women.

Adolescent↗
PubMed1993

Accumulation of salicylic acid and indomethacin in isolated proximal tubular cells of the rat kidney.

The handling and accumulation of salicylic acid (SA) and indomethacin was examined in freshly isolated proximal tubular (PT) cells of the rat kidney in order to determine whether these cells provide a useful tool for studying accumulation of nonsteroidal anti-inflammatory drugs. A PT cell suspension was prepared by collagenase digestion, followed by filtration and isopycnic centrifugation. SA uptake was concentration-dependent and could be inhibited by probenecid. SA accumulated in the PT cells, and therefore, uptake is probably an active process. In the presence of probenecid, no SA accumulation was observed. Indomethacin uptake increased with time up to 2 min. Thereafter, a sharp decrease occurred, probably caused by inhibition of the oxidative phosphorylation. In the presence of probenecid, uptake was significantly reduced and no longer time-dependent. Indomethacin accumulated in the PT cells by a factor of more than 25. In the presence of probenecid, accumulation was decreased but was still considerable (approximately 10), probably as a result of binding to cellular protein. We conclude that as a result of carrier-mediated transport which is probenecid-sensitive, SA and indomethacin accumulate in the PT cells. The observed accumulation values are in accordance with previously observed values in the isolated perfused rat kidney. Therefore, freshly isolated PT cells appear to be a simple and useful model for studying the accumulation process of drugs like SA and indomethacin.

Animals↗
PubMed2006

Bioactivation of carboxylic acid compounds by UDP-Glucuronosyltransferases to DNA-damaging intermediates: role of glycoxidation and oxidative stress in genotoxicity.

Nonenzymatic modification of proteins by acyl glucuronides is well documented; however, little is known about their potential to damage DNA. We have previously reported that clofibric acid undergoes glucuronidation-dependent bioactivation to DNA-damaging species in cultured mouse hepatocytes. The aim of this study was to investigate the mechanisms underlying such DNA damage, and to screen chemically diverse carboxylic acid drugs for their DNA-damaging potential in glucuronidation proficient murine hepatocytes. Cells were incubated with each aglycone for 18 h, followed by assessment of compound cytotoxicity using the MTT assay and evaluation of DNA damage using the Comet assay. Relative cytotoxic potencies were ketoprofen > diclofenac, benoxaprofen, nafenopin >> gemfibrozil, probenecid > bezafibrate > clofibric acid. At a noncytotoxic (0.1 mM) concentration, only benoxaprofen, nafenopin, clofibric acid, and probenecid significantly increased Comet moments (P < 0.05 Kruskal-Wallis). Clofibric acid and probenecid exhibited the greatest DNA-damaging potency, producing significant DNA damage at 0.01 mM concentrations. The two drugs produced maximal increases in Comet moment of 4.51 x and 2.57 x control, respectively. The glucuronidation inhibitor borneol (1 mM) abolished the induction of DNA damage by 0.5 mM concentrations of clofibric acid and probenecid. In an in vitro cell-free system, clofibric acid glucuronide was 10 x more potent than glucuronic acid in causing DNA strand-nicking, although both compounds showed similar rates of autoxidation to generate hydroxyl radicals. In cultured hepatocytes, the glycation inhibitor, aminoguanidine, and the iron chelator, desferrioxamine mesylate, inhibited DNA damage by clofibric acid, whereas the free radical scavengers Trolox and butylated hydroxytoluene, and the superoxide dismutase mimetic bis-3,5-diisopropylsalicylate had no effect. In conclusion, clinically relevant concentrations of two structurally unrelated carboxylic acids, probenecid and clofibric acid, induced DNA damage in isolated hepatocytes via glucuronidation- dependent pathways. These findings suggest acyl glucuronides are able to access and damage nuclear DNA via iron-catalyzed glycation/glycoxidative processes.

Animals↗
PubMed2001

Co-composting of pharmaceutical wastes in soil.

AIMS: Soils at a commercial facility had become contaminated with the pharmaceutical chemical residues, Probenecid and Methaqualone, and required remediation. METHODS AND RESULTS: Soil composting was investigated as an alternative to incineration for treatment. In laboratory trials, a factorial experimental design was used to evaluate organic matter amendment type and concentration, and incubation temperature. In pilot scale trials, Probenecid was reduced from 5100 mg kg(-1) to < 10 mg kg(-1) within 20 weeks in mesophilic treatments. An 8 tonne pilot scale treatment confirmed that thermophilic composting was effective under field conditions. In the full-scale treatment, 180 tonnes of soil were composted. Initial concentrations of the major contaminants in the full-scale compost treatment were 1160 mg kg(-1) and 210 mg kg(-1), for Probenecid and Methaqualone, respectively. Probenecid concentration reached the target level of 100 mg kg(-1) in 6 weeks, and removal of Methaqualone to < 100 mg kg(-1) was achieved after 14 weeks. CONCLUSION: Co-composting was effective in reducing soil concentrations of Probenecid and Methaqualone residues to acceptable values. SIGNIFICANCE AND IMPACT OF THE STUDY: Co-composting is a technology that has application in the remediation of pharmaceutical contaminants in soil.

Australia↗
PubMed1984

Release of cAMP from a renal epithelial cell line.

LLC-PK1 is an established porcine renal cell line with epithelial characteristics. Upon hormonal stimulation by vasopressin, LLC-PK1 cells release adenosine 3',5'-cyclic monophosphate (cAMP) into the medium. Release of cAMP is inhibited by the organic anion transport inhibitor probenecid and by cold phosphodiesterase inhibitors and iodoacetate but not by prostaglandins A1 or E1. The kinetics of release are first order, and cAMP analogues do not induce the release of cAMP. When grown on cellulose filters, monolayers of LLC-PK1 have morphological characteristics of transporting epithelia (apical microvilli and intercellular tight junctions) and maintain a transepithelial potential difference. Stimulation of such monolayers by vasopressin elicits probenecid-sensitive release of cAMP into the medium bathing the apical surface. Smaller quantities of cAMP are released from the basolateral surface, but release in this direction is not inhibited by probenecid. In contrast, release of cAMP from the nonepithelial cell line BHK is symmetrical and is symmetrically inhibited by probenecid. Probenecid-sensitive release of cAMP from LLC-PK1 is thus a function of the apical (brush-border) membrane.

Animals↗
PubMed1998

Peritubular transport of ochratoxin A in rabbit renal proximal tubules.

The transport of the nephrotoxic mycotoxin ochratoxin A across the renal peritubular membrane was examined in suspensions of rabbit renal proximal tubules. Ochratoxin A transport across the peritubular membrane was a high-affinity, low-capacity carrier-mediated process with a Jmax value of 0.12 +/- 0.4 nmol/mg of protein/min and a Km value of 1.4 +/- 0.1 microM. The apparent Michaelis constants for inhibition of [3H]para-aminohippurate (PAH) uptake by ochratoxin A inhibition was 1.5 microM, which is similar to the Km value for ochratoxin A uptake in tubule suspensions and suggests that ochratoxin A could be a substrate for the organic anion pathway. The capacity and affinity for peritubular ochratoxin A transport were 40-fold lower and > 100-fold greater, respectively, than those measured for the peritubular uptake of [3H]PAH in tubule suspensions. A concentration of 2.5 mM PAH, which reduced the uptake of [3H]PAH by 90%, reduced ochratoxin A uptake by only 40% to 50%, whereas probenecid concentrations of 0.6 to 2 mM reduced ochratoxin A accumulation in tubule suspensions up to approximately 80% to 90%. This probenecid-sensitive, PAH-insensitive uptake of ochratoxin A suggested that at least one mediated pathway other than the organic anion transporter was involved in the peritubular uptake of this mycotoxin. A 2 mM concentration of the fatty acid octanoate and 1.5 mM concentration of the nonsteroidal anti-inflammatory agent piroxicam were as effective as probenecid in blocking ochratoxin A uptake. The apparent Ki values for inhibition of ochratoxin A uptake by probenecid, piroxicam and octanoate were 30.5 +/- 7.9, 23.2 +/- 10.4 and 81.5 +/- 8.7 microM, respectively. The ability of octanoic acid to inhibit ochratoxin A transport to the same extent as probenecid and a greater extent than PAH suggests that a separate fatty acid transport pathway may be involved in the accumulation of ochratoxin A by suspensions of rabbit renal proximal tubules.

Animals↗
PubMed1983

Some factors affecting the concentrations of para-hydroxyphenylacetic acid and meta-hydroxyphenylacetic acid in the mouse caudate nucleus.

Acid hydrolysis of mouse caudate homogenates results in a significantly increased concentration of para-hydroxyphenylacetic acid (p-HPAA). Thus p-HPAA appears to be significantly present as an acid-labile conjugate in the mouse caudate nucleus. Saline injection also increased the concentration of the acid metabolite of the tyramines. The subcutaneous injection of either meta-hydroxyphenylacetic acid (m-HPAA) or p-HPAA or both produced at 0.5 hr and 2.0 hr large increases in the mouse caudate nucleus concentrations of m- and/or p-HPAA. Similarly at 2.0 hr the injection of a combination of para- and meta-tyramine caused large increases in the acid metabolite concentrations. Probenecid, at a dose of 500 mg/kg, increased striatal p-HPAA and m-HPAA concentrations. Probenecid, injection prior to the administration of p-HPAA and m-HPAA, did not reduce the increased concentrations of these two acid metabolites previously observed after the administration of the acid metabolites alone. It thus appears that p-HPAA and m-HPAA are transported from the brain by a probenecid-sensitive mechanism, but in the presence of high blood concentrations, p-HPAA and m-HPAA may enter the brain by a mechanism that is not affected by probenecid.

Animals↗
PubMed2001

Influence of multidrug resistance (MDR) proteins at the blood-brain barrier on the transport and brain distribution of enaminone anticonvulsants.

Previous in vitro studies evaluating the permeability of enaminones suggested that their blood-brain barrier (BBB) transport might be influenced by the presence of an efflux mechanism. Therefore, transport mechanisms responsible for these anticonvulsants across the BBB were examined. The transport of enaminones (1 x 10(-4) M) were evaluated over 120 min with verapamil (50 microM) and probenecid (100 microM) using bovine brain microvessel endothelial cells (BBMECs) to assess the role of multidrug resistant (MDR) transport proteins [i.e., P-glycoprotein (Pgp) and MDR protein 1 (MRP1)] on efflux, respectively. Uptake studies in the presence and absence of rhodamine 123 (R123; 3.2 and 5.0 microM) were also performed in a Pgp overexpressing cell line, MCF-7/Adr. Select enaminone esters (12.5 mg/kg) were administered intravenously to mdr 1 a/b (+/+), mdr 1 a/b (-/-) knockout and probenecid pretreated mice (20 +/- 5g). Enaminones and R123 were assayed with validated ultraviolet and fluorescence high-performance liquid chromatography methods, respectively. Verapamil and probenecid significantly ( p>0.05) inhibited the transport of select enaminone esters across BBMECs. Two enaminones caused a statistically significant increase in the uptake of R123 in MCF-7/Adr cells. Concentrations of select enaminones in mdr 1 a/b (-/-) mice brains were significantly higher ( p<0.05) compared with those in mdr 1 a/b (+/+) mice brains; however, no differences were observed in probenecid pretreated animals. Taken together, these results strongly suggest that Pgp may influence enaminone transport at the BBB and hence affect epilepsy treatment with these agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1981

Serotonin and dopamine disturbances in patients with unipolar depression and Parkinsonism.

Probenecid was administered to 7 unipolar depressed patients, 7 parkinsonians and 7 extrapyramidal patients with senile dementia matched for age and sex. Before and after the administration of probenecid, the levels of 5 hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) were determined in the cerebrospinal fluid (CSF) of all patients in order to study the central turnover rate of serotonin and dopamine. Unipolar depressed patients showed a significantly lower increase in CSF 5HIAA levels after probenecid than parkinsonians. Patients with Parkinsonism had a reduced increment of CSF HVA levels following probenecid administration when compared to unipolar depressed and extrapyramidal patients with senile dementia.

Brain↗
PubMed1984

Renal excretion of an angiotensin I converting enzyme inhibitor (SA-446) in dogs.

The renal excretory mechanism of an orally active inhibitor of angiotensin converting enzyme (SA-446) was examined in anesthetized dogs. Parenteral administration of this compound resulted in production of constant levels of about 2 mg/l in the plasma (PSA) and the urine concentration was 726 +/- 200 mg/l, a level significantly higher than that in the plasma. Renal clearance of SA-446 (CSA) was 2.24 +/- 0.34 ml/g X min and was significantly higher than GFR. The clearance ratio (CSA/GFR) of over 1.0 was indicative of a net tubular secretion. Administration of probenecid resulted in a significant rise in PSA and in a significant decrease in urinary excretion but with no change in the plasma protein binding ratio. CSA decreased significantly from 2.24 +/- 0.34 to 0.71 +/- 0.14 ml/g X min. The inhibitory action of SA-446 (0.02 mg/kg, i.v.) on the pressor response to angiotensin I disappeared at about 50 min, this action being maintained for about 2 h in the probenecid pretreated dog. Since probenecid is a competitive inhibitor of organic anion secretory transport, our results show the net tubular secretion of SA-446, via organic anion transport systems. Prolongation of the action of SA-446, as induced by probenecid may be due to the increase of plasma concentration, by the inhibition of tubular secretion.

3-Mercaptopropionic Acid↗
PubMed1994

Nonlinear renal excretion of theophylline and its metabolites, 1-methyluric acid and 1,3-dimethyluric acid, in rats.

Plasma pharmacokinetics and renal excretion of theophylline (TP) and its metabolites were investigated in rats. Plasma concentrations of TP declined in a monoexponential manner, while those of 1-methyluric (MU) and 1,3-dimethyluric (DMU) declined in a biexponential manner upon respective i.v. bolus injection of each compound at 6 mg/kg dose. The total body clearances (CLt) of the metabolites were 4-6 fold larger than that of TP, while the distribution volumes of them at steady-state (Vdss) were 40-50% smaller than that of TP. The metabolites showed their plasma peaks in 30 min after i.v. injection of TP indicating very rapid metabolism of TP. Metabolism of TP to DMU was more than fourfold faster than that to MU. Renal excretion of TP and its metabolites was studied in urine flow rate (UFR)-controlled rats. The renal clearance (CLr) of TP was inversely related to plasma TP concentrations, and much smaller than the glomerular filtration rate (GFR) suggesting tubular secretion and profound reabsorption in the renal tubule. The CLr of each metabolite also showed that inverse relationship, but far exceeded GFR suggesting that tubular secretion plays a major role in their elimination. The CLr of the metabolites were reduced to less than GFR by i.p. injection of probenecid (142.7 mg/kg). It supports that the metabolites are secreted in the renal tubule, and suggests that they share a common transport system in their secretion processes with probenecid. On the other hand, the CLr of TP was not affected significantly by the probenecid treatment. Considering the inverse relationship of TP between the CLr and its plasma concentrations, no effect of probenecid on CLr of TP is most likely due to negligible contribution of the secretion to the overall CLr of TP.

Animals↗
PubMed1978

Aspects of influx and efflux of homovanillic acid of rat cerebrospinal fluid.

In rats, different methods of perfusion (lumbar-cisternal or ventricular-cisternal) with artificial cerebrospinal fluid were performed at velocities of about 30 and 180 microliter/min. Levels of homovanillic acid (HVA) in the outflow were assayed with a semiautomated fluorimetric technique. Intravenous administration of 20 microgram HVA did not substantially enhance the outflow of this acid, indicating that in our preparations HVA found in the perfusate is of central origin. In the lumbar-cisternal preparation probenecid (200 mg/kg, i.p.) was found to inhibit the efflux of a significant fraction of HVA added to the medium, at both perfusion rates. The proportions of HVA eliminated by a probenecid sensitive transport was much higher at the lower rate of perfusion. Following probenecid the increase of endogenous HVA in the ventricular-cisternal perfusate was higher at a lower rate of perfusion. We determined the turnover rate of HVA in the whole brain and compared this value with the HVA outflow in the various preparations. The highest efflux of HVA was found in the ventricular-cisternal preparation during probenecid treatment and did not appear to be dependent upon the rate of perfusion. A maximal value of 3.5% of HVA formed in the central nervous system was found to be released into the cerebrospinal fluid.

Animals↗
PubMed1982

Monoamine metabolite concentrations in the cerebrospinal fluid of normal and narcoleptic dogs.

Because of the similarity between human and canine narcolepsy, an animal model has emerged with which to investigate the neurochemical basis of the disease. In this study, in vivo differences in cerebral neurotransmitter function between normal and affected dogs were measured by comparing, before and after probenecid administration, the concentrations in cisternal cerebrospinal fluid of the monoamine metabolites 5-hydroxyindoleacetic acid, homovanillic acid, 3,4-dihydroxyphenylacetic acid, and 3-methoxy-4-hydroxyphenylethylene glycol. Cisternal cerebrospinal fluid was collected from the cisterna magna of anaesthetized animals, and samples were analyzed for the metabolites and probenecid using combined gas chromatography-mass spectrometry. The concentrations of both the conjugated and non-conjugated forms of each of the metabolites were determined in all samples and the role of conjugation in cerebral monoamine metabolism is discussed. Before probenecid treatment, comparisons of metabolite concentrations in samples from normal versus narcoleptic dogs showed significantly lower amounts of the dopamine and of the 5-hydroxytryptamine metabolites in CSF from the affected animals. After probenecid administration, the concentrations in the CSF of all the metabolites increased. However, the amounts of 5-hydroxyindoleacetic acid, and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol, in samples from narcoleptic dogs were significantly lower than those found in samples from normal dogs. The implications of these results for our understanding of the neurochemical basis of REM sleep initiation and for treatment of narcolepsy/cataplexy are discussed.

3,4-Dihydroxyphenylacetic Acid↗