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PubMed1977

Metabolic clearance of furosemide in the rat.

The effect of probenecid on the metabolic clerance of [35S]furosemide was examined in Sprague-Dawley rats by the single injection technique. Metabolic clearance was found to decrease from 1.74+/-0.11 ml/min in animals which received furosemide alone to 1.06+/-0.10 ml/min in animals which received both furosemide and probenecid. Estimation of urine and biliary clearance revealed that approximately two-thirds of the metabolic clearance was due to urinary clearance and one-third to biliary clearance, and that both decreased after probenecid administration. Thin-layer chromatographic studies indicated furosemide was metabolized by both liver and kidney but also secreted in unchanged form in urine, and that the proportion of unaltered furosemide to metabolite in urine was increased by probenecid. Further studies indicated that phenobarbital pretreatment had no effect on either hepatic or renal clearance of furosemide and that bile clearance was not altered by acute bilateral nephrectomy.

Animals↗
PubMed1999

Both Pgp and MRP1 activities using calcein-AM contribute to drug resistance in AML.

Thirteen cell lines with different levels of Pgp and MRP1 expression were used to assess the ability of calcein-AM uptake and calcein efflux to measure Pgp and MRP1 functions, respectively. There was a good correlation between MRP1 expression and the modulatory effect of probenecid (a specific modulator of MRP1) on the calcein efflux (r = 0.91, p = 0.0003) and between Pgp expression and the modulatory effect of CsA on calcein-AM uptake (r = 0.96, p < 0.0001). On light of the high correlations for both proteins, we tested calcein-AM uptake and efflux in fresh myeloid leukemic cells. In 53 AML patients, there was also a good correlation between MRP1 expression (measured by RT/PCR and by MRPm6 expression by flow cytometry) and the modulatory effect of probenecid on the calcein fluorescence (r = 0.92, p < 0.0001) and between Pgp expression as measured by UIC2 antibody binding on flow cytometry and the modulatory effect of CsA on calcein-AM uptake (r = 0.83, p < 0.0001). Pgp activity was higher in CD34+ leukemia than in CD34- leukemia (2.26 +/- 1.50 vs 1.46 +/- 1.21 respectively, p = 0.003) and MRP1 activity was higher in CD34- leukemia than in CD34+ leukemia (1.77 +/- 0.40 vs 1.4 +/- 0.29 respectively, p = 0.004). Pgp expression and activity (p = 0.004 and p = 0.01, respectively), MRP1 activity (p = 0.03) but not MRP1 expression were prognostic factors for achievement of CR. The effect of probenecid and CsA together were higher than the effect of either probenecid or CsA alone on calcein-AM uptake. These results suggest that functional testing (with calcein-AM +/- modulators) for the presence of both MRP1 and Pgp activities is of prognostic value and that MRP1 contributes to drug resistance in AML.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Effect of para-aminohippurate on the efflux of valproic acid from the central nervous system of the rabbit.

Recently we investigated the mechanisms mediating the transport of valproic acid (VPA) between blood and brain. In one study efflux of valproic acid (VPA) from rabbit brain was inhibited by probenecid. Efflux of VPA decreased when probenecid was given intravenously but not when probenecid was given by ventriculocisternal (VC) perfusion indicating that the major site of probenecid-sensitive transport was at the brain capillary endothelium and not at the choroid plexus. In another study VPA transport into rat brain was inhibited by para-aminohippurate (PAH). The purpose of the present study were to determine (a) if the efflux of VPA from rabbit brain was also inhibited by PAH, and (b) whether efflux of VPA could occur at the choroid plexus via an PAH-selective transport system. Six control rabbits received VPA by intravenous infusion and tracer concentrations of [3H]VPA and [14C]PAH by VC perfusion. Rabbits in the PAH group (n = 6) received identical treatment with VPA, tracer concentrations of [3H]VPA and [14C]PAH and, in addition, received 20 mM PAH by VC perfusion. PAH had no effect on the VC extraction ratio of [3H]VPA or the steady-state brain concentration of intravenously administered VPA. It is concluded that the efflux of VPA at the rabbit blood-brain barrier is mediated by a transporter different from the PAH-like transporter responsible for the uptake of VPA into rat brain. In addition, the finding that VC perfusion with PAH had no effect on the VC extraction of [3H]VPA provides further evidence that the choroid plexus plays a negligible role in removal of VPA from the CNS.

Animals↗
PubMedDate not supplied

Discrimination of transport systems for methylmercury-cysteine uptake in rat erythrocytes by inhibitors and other factors.

The transport systems for methylmercury-cysteine (MeHgCys) uptake by isolated erythrocytes from rats were studied at 5 degrees C. Probenecid was used to test the organic acid transport system at different concentrations. While inhibiting the organic acid transport system by probenecid (0.25 mM), the following agents were used to determine other transport systems for MeHgCys uptake: (1) ouabain and sodium fluoride (NaF) were used to test the active transport system; (2) 4,4'-diisothiocyano-2,2'-stilbenendisulphonic acid (DIDS) and N-ethylmaleimide (NEM) were used to test the C1-ion transort system; (3) colchicine and vinblastine were used t o test the microtubule system; (4) hexanol was used to test the protein-mediated trasport systems and the non-electrolyte diffusion; (5) valinomycin was used to test the effect of the membrane potential on MeHgCys uptake. Furthermore, the effects of NH4+, Li+ and Na+ in the buffer on MeHgCys uptake were examined with or without probenecid. The results showed that most of MeHgCys was transported by the organic acid transport system. Colchicine and vinblastine stimulated MeHgCys uptake. NH4+, Li+ and Na+ ions could stimulate MeHgCys uptake with or without probenecid. Meanwhile, a small amount of MeHgCys was transported by means of the non-electrolyte diffusion which was stimulated by hexanol. Furthermore, DIDS could stimulate MeHgCys uptake and the transport systems for MeHgCys uptake were sensitive to the membrane potential.

Animals↗
PubMed1982

Ceftizoxime kinetics and renal handling.

The kinetics and renal handling of ceftizoxime were examined after intravenous and intramuscular injection and the effect of probenecid on its excretion was investigated. Peak serum level after 1000 mg IV was 60.5 microgram/ml and half-life (t 1/2) was 1.4 hr. Peak serum level (40.9 microgram/ml) was reached 1 hr after 1000 mg IM. When probenecid was added to the 1000-mg IM dose the peak level was 44.3 microgram/ml at 1 hr and serum levels at 2, 4, 6, and 8 hr were all higher than after ceftizoxime alone (P less than 0.01). The 1.85-hr t 1/2 of ceftizoxime alone was extended to 2.29 hr when probenecid was added. Ceftizoxime was shown to be actively secreted by the renal tubule; this secretion was decreased by probenecid.

Anti-Bacterial Agents↗
PubMed1997

Natriuretic efficiency of frusemide as a consequence of drug input rate.

AIMS: The aim of the present study was to investigate the influence of the rate of delivery of frusemide to its site of action on the effect and efficiency of the drug. METHODS: Frusemide 30 mg was administered as a bolus dose, a slow-rate infusion and a bolus dose in combination with 2 g of probenecid in a three way cross-over design to seven healthy volunteers. Urinary volume and contents of frusemide and sodium were measured in samples collected over 10 h. RESULTS: Total natriuretic response was 40% higher (P < 0.001) after the infusion and 20% higher (P < 0.05) after the combined treatment with probenecid, as compared with the bolus dose. Total natriuretic efficiency did not differ between the infusion (0.013 mmol microg(-1)) and the combined treatment with probenecid (0.015 mmol microg(-1)), but was significantly higher as compared with the bolus dose (0.009 mmol microg(-1)). Natriuretic effect data were modeled according to the sigmoid Emax model and the frusemide excretion rate with maximum efficiency (ER(effmax)) was calculated from the estimated parameters. For both the frusemide infusion and the combined treatment with probenecid, the time course of delivery of frusemide into the urine consistently approached ER(effmax) more closely than was the case for the bolus dose. The natriuretic effect vs frusemide excretion rate curves were shifted to the right, and the estimated values of the sigmoid Emax model were higher for EC50 and lower for the slope factor after the bolus dose, which may indicate tolerance development for this treatment. CONCLUSIONS: Slowing the delivery of frusemide to the site of action increased the efficiency of the drug, leading to an increased natriuretic response.

Adult↗
PubMed2006

Renal handling of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, in rabbits in comparison with meropenem.

The plasma half-life of CS-023 (RO4908463), a novel parenteral carbapenem antibiotic, is longer than that of meropenem in animals and humans. To address this issue, renal clearance studies were conducted in rabbits. A constant rate infusion of CS-023 and meropenem was conducted in male Japanese White rabbits. Concentrations in the plasma, urine and renal cortex were measured to evaluate renal clearance and renal tissue uptake. CS-023 showed a clearance ratio (renal clearance/glomerular filtration rate) of around 1, which was not affected by co-administration of probenecid or p-aminohippurate. On the other hand, meropenem exhibited a clearance ratio of around 3, which was significantly decreased to 1 by co-administration of probenecid. p-Aminohippurate, in contrast, had no effect. The renal cortex/plasma concentration ratio of CS-023 was around 0.6 with or without probenecid co-administration. This ratio of meropenem was around 3, which was decreased significantly by co-administration of probenecid to around 0.6. These data suggest that meropenem is secreted in the renal tubules via organic anion transporters, but CS-023 is not. The present findings in rabbits would indicate that a lack of renal tubular secretion of CS-023 is a reason for the long plasma half-life compared with meropenem.

Animals↗
PubMed1984

Hepato-renal cooperation in biotransformation, membrane transport, and elimination of cysteine S-conjugates of xenobiotics.

Biosynthesis of N-acetylcysteine S-conjugates of xenobiotics, mercapturic acids, occurs via inter-organ metabolism of the corresponding glutathione derivatives (Inoue, M., Okajima, K., & Morino, Y. (1982) Hepatology 2, 311-316). To elucidate the mechanism of mercapturate biosynthesis and its urinary elimination, hepato-renal cooperation in the enzymic processing and membrane transport of cysteine derivatives was studied in isolated hepatocytes, perfused liver and renal cortical tubules. Isolated hepatocytes rapidly accumulated S-benzylcysteine by a carrier-mediated mechanism and metabolized it to the N-acetylcysteine conjugate. Experiments in perfused rat liver revealed that, upon infusion of S-benzylcysteine, N-acetyl-S-benzylcysteine appeared in the effluent perfusate and hepatic excretion of this mercapturate was inhibited by simultaneous infusion of probenecid, an inhibitor of the organic anion transport system. Isolated renal cortical tubules actively accumulated N-acetyl-S-benzylcysteine by a dinitrophenol-sensitive, carrier-mediated mechanism which was competitively inhibited by probenecid and hippuric acid. These and other results indicate that a cysteine S-conjugate in plasma is rapidly taken up by the liver and converted to the N-acetyl derivative which is translocated into plasma via a probenecid-sensitive transport system in hepatic sinusoidal membranes. The mercapturic acid excreted in plasma is transferred to the kidney and finally excreted into urine by a probenecid sensitive transtubular transport system for organic anions in renal cortical tubules. Hepato-renal cooperation in metabolic conjugation and membrane transport of these intermediates appears to constitute an important process in mercapturate biosynthesis and urinary excretion of the final metabolites.

Acetylation↗
PubMed1991

Turnover of dopamine and serotonin and their metabolites in the striatum of aged rats.

Turnover of dopamine (DA), serotonin [5-hydroxytryptamine (5-HT)], and their metabolites has been measured in adult and aged rats. Turnover rates of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxy-3-indoleacetic acid (5-HIAA) have been assayed from the disappearance rates after blocking by pargyline inhibition of monoamine oxidase (MAO) and from the accumulation rates by probenecid inhibition of the probenecid-sensitive transport system. DA and 5-HT turnover rates have been measured as accumulation rates of 3,4-dihydroxyphenylalanine and 5-hydroxytryptophan, respectively, after central decarboxylase inhibition by 3-hydroxybenzylhydrazine (NSD-1015) and as accumulation rates of DA and 5-HT after pargyline inhibition of MAO. The DA turnover rate after NSD-1015 was 23.9% lower in aged rats than in adults, whereas after pargyline there was no significant difference between the two age groups. The HVA fractional rate constant and turnover after pargyline were lower in aged rats than in adults, and HVA turnover after probenecid was higher in aged rats than in adults. The DOPAC-HVA pathway seems to be reinforced at the expense of DOPAC conjugation. In aged and adult rats whose 5-HT steady-state levels were not statistically different, the 5-HT turnover rate after pargyline and NSD-1015 treatment was lower in aged rats than in adults. An increase of 5-HIAA levels after pargyline and probenecid treatment in aged rats could be due to the handling stress.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2003

Pharmacokinetics of 5 (and 6)-carboxy-2',7'-dichlorofluorescein and its diacetate promoiety in the liver.

Hepatic disposition of 5 (and 6)-carboxy-2',7'-dichlorofluorescein (CDF) and its diacetate promoiety (CDFDA) was studied in isolated perfused rat livers. Livers from Wistar wild-type and multidrug resistance-associated protein (Mrp)2-deficient (TR(-)) rats were perfused with CDF in the presence or absence of probenecid. Probenecid decreased the recovery of CDF in bile approximately 4-fold in wild-type livers (65 +/- 8% versus 15 +/- 2% of dose over 2 h). In livers from TR(-) rats, CDF was not excreted into bile and probenecid decreased perfusate CDF concentrations in a concentration-dependent manner, in part due to inhibition of Mrp3. Plasma membrane vesicles from rat Mrp2- or Mrp3-transfected Sf9 cells were used to confirm that CDF is a substrate for Mrp2 and Mrp3; probenecid inhibited the transport of CDF by Mrp2 and Mrp3 in a concentration-dependent manner. CDF uptake in collagen sandwich-cultured rat hepatocytes was temperature-dependent and saturable (K(m) = 22 +/- 10 microM; V(max) = 97 +/- 9 pmol/min/mg protein). Uptake of CDF in sandwich-cultured rat hepatocytes was impaired significantly by bromosulfophthalein, a substrate for organic anion-transporting polypeptides (Oatps), but was not modulated by specific Oatp2 or organic anion transporter (Oat) substrates. CDFDA uptake was not saturable, temperature-dependent, or impaired by inhibitors. The hydrolysis of CDFDA to CDF is mediated by basic pH and esterases in biological media. CDFDA passively diffuses into hepatocytes where it is hydrolyzed to CDF. In contrast, CDF appears to be taken up by Oatp-mediated transport into rat hepatocytes and effluxed via Mrp2 into bile and via Mrp3 into sinusoidal blood.

Acetates↗
PubMed2005

Influence of efflux transporters on the accumulation and efflux of four quinolones (ciprofloxacin, levofloxacin, garenoxacin, and moxifloxacin) in J774 macrophages.

Ciprofloxacin is subject to efflux from J774 macrophages through a multidrug resistance-related protein-like transporter (J. M. Michot, F. Van Bambeke, M. P. Mingeot-Leclercq, and P. M. Tulkens, Antimicrob. Agents Chemother. 48:2673-2682, 2004). Here, we compare ciprofloxacin to levofloxacin, garenoxacin, and moxifloxacin for transport. At 4 mg/liter, an apparent steady state in accumulation was reached after 30 to 60 min for all quinolones but to quite different levels (approximately 3, 5, 10, and 16 fold). Accumulation of ciprofloxacin was increased (to about 16 to 20 fold) by ATP depletion, increase in extracellular concentration, and the addition of probenecid, gemfibrozil, or MK571 (but not verapamil or GF120918). These treatments did not affect the accumulation of moxifloxacin. Levofloxacin and garenoxacin showed an intermediate behavior. Efflux of ciprofloxacin was slowed down by probenecid (half-life, 7.2 versus 1.6 min). Moxifloxacin efflux was faster and unaffected by probenecid (half-lifes, 0.27 versus 0.33 min). Efflux of levofloxacin and garenoxacin was modestly decreased by probenecid (1.5 and 2.1 fold). Accumulation of 14C-labeled ciprofloxacin was increased by unlabeled ciprofloxacin and moxifloxacin, but moxifloxacin was two times less potent. Accumulation of moxifloxacin at 4 degrees C was almost identical to that at 37 degrees C, whereas that of ciprofloxacin was minimal (levofloxacin and garenoxacin showed intermediate behaviors). Cells subjected to thermal shock (56 degrees C; 10 min) accumulated all quinolones at a similar level (16 to 23 fold). We conclude that moxifloxacin is apparently not subject to efflux from J774 macrophages, even though it can interact with the ciprofloxacin transporter. Levofloxacin and garenoxacin are partially effluxed. Data suggest that efflux plays an important role in the differential accumulation of quinolones by J774 macrophages.

Anti-Infective Agents↗
PubMed1987

Cimetidine transport in isolated luminal membrane vesicles from rabbit kidney.

Experiments were conducted to study the transport of the histamine H2-receptor antagonist, cimetidine, in luminal membrane vesicles prepared from rabbit renal cortex. Cimetidine accumulated in the vesicles with time. Cimetidine uptake was sensitive to changes in vesicle size, suggesting that the compound is transported into an osmotically reactive intravesicular space. Its rate of uptake could be described by both a saturable and a nonsaturable process. The Km was 4.6 +/- 4.0 microM and the Vmax was 6.8 +/- 2.3 pmol X s-1 X mg protein-1 (mean +/- SD, n = 4). N1-methylnicotinamide (NMN), cimetidine, cimetidine sulfoxide, and ranitidine inhibited the uptake of cimetidine. Cimetidine uptake in the presence of an outwardly directed proton gradient was enhanced in vesicles preloaded with a higher concentration of unlabeled cimetidine (2.4 X 10(-4) M). An outwardly directed proton gradient enhanced the uptake of cimetidine to values exceeding its equilibrium accumulation. Uptake stimulated in this way could be inhibited by the cation, NMN, the bases, ranitidine, and cimetidine sulfoxide, and interestingly, by the anion, probenecid. The effect of probenecid did not appear to be due to nonspecific effects on membrane binding, membrane potential, or vesicle size. These data are consistent with data obtained in isolated perfused proximal tubules, demonstrating that probenecid inhibits cimetidine transport. The data in this study suggest that the effect of probenecid on cimetidine transport specifically involves the transporter in the luminal membrane.

Animals↗
PubMed1999

Fluid secretion by isolated Malpighian tubules of Drosophila melanogaster Meig.: effects of organic anions, quinacrine and a diuretic factor found in the secreted fluid.

Para-aminohippuric acid (PAH, 0.2 and 1 mmol l(-)(1)) had no effect on the basal fluid secretion rate (FSR) of isolated Malpighian tubules of Drosophila melanogaster Meig. and did not affect stimulation of the FSR induced by adenosine 3',5'-monophosphate (cAMP). Phenol Red (phenolsulphonphthalein, PSP; 0.5 and 1 mmol l(-)(1)) slowed the FSR and abolished stimulation of the FSR by cAMP. Diodrast (1 mmol l(-)(1)) slightly, but significantly, reduced the FSR and greatly reduced the stimulation of the FSR normally provoked by cAMP and by the 3',5'-monophosphates of guanosine (cGMP), inosine (cIMP) and uridine (cUMP). However, stimulation of the FSR by the 3', 5'-monophosphate of cytidine (cCMP) was little affected by diodrast. Probenecid (0.2 or 1 mmol l(-)(1)) consistently stimulated the FSR, on average by approximately 25 %, but did not markedly inhibit the subsequent stimulation of the FSR by cAMP, cGMP or cIMP. However, the FSR of tubules stimulated by cGMP was temporarily lowered by probenecid. Quinacrine (0.1 mmol l(-)(1)) slowed basal FSR by an average of approximately 30 %, but subsequent stimulation of the FSR by cAMP was not noticeably affected. Both 0.1 mmol l(-)(1) cAMP and 1 mmol l(-)(1) probenecid stimulated adenylate cyclase activity in extracts of Malpighian tubules, but cIMP, cGMP, cUMP and diodrast were without effect in this regard. Uptake of radioactivity from a solution containing 500 nmol l(-)(1) [(3)H]cAMP and 9.5 micromol l(-)(1) cAMP was reduced by more than 90 % by 1 mmol l(-)(1) PSP, by approximately 40 % by 0.2 mmol l(-)(1) probenecid, by 36 % by 1 mmol l(-)(1) diodrast and by 30 % by 1 mmol l(-)(1) PAH. Neither 0.01 mmol l(-)(1) ouabain nor 0.1 mmol l(-)(1) quinacrine affected the uptake of [(3)H]cAMP by the Malpighian tubules. Fluid secreted by isolated Malpighian tubules of Drosophila melanogaster contains a factor that stimulated the FSR on average by approximately 50 %. The presence in the secreted fluid of cGMP at a concentration of 8.3 micromol l(-)(1) did not explain the stimulatory effect on FSR. These results support the existence of a carrier-mediated uptake of cyclic nucleotides into the Malpighian tubules of Drosophila melanogaster, possibly involving a multispecific transporter.

Adenylyl Cyclases↗
PubMed1983

Determinants of the overall response to furosemide: pharmacokinetics and pharmacodynamics.

After an oral or i.v. dose of furosemide, there is considerable interindividual variability in the amount of unchanged drug delivered into the urine. On the average, approximately half as much reaches the intraluminal site of action with an oral compared with an i.v. dose. However, the natriuretic response to the same dose administered by either route is virtually the same. Similarly, after pretreatment with probenecid, the same total amount of furosemide in urine causes a greater overall response. It has been presumed that this paradox is accounted for by differences in rate of delivery of furosemide to the active site such that after an oral dose or after pretreatment with probenecid, amounts of drug are at the "steep" portion of the dose-response curve for longer periods of time. Our analysis shows that this is not the case. For furosemide, the amount of diuretic delivered into the urine that is maximally efficient (21.5 micrograms/min) is considerably less than the amount causing half-maximal response (69.8 micrograms/min). Oral administration or pretreatment with probenecid maintains drug close to this maximally efficient amount more persistently than does i.v. administration. By so doing, total response to an oral dose approaches that of i.v. dosing despite delivering half the amount of drug to the active site, and after probenecid an i.v. dose causes a greater response than i.v. dosing alone despite delivering the same amount of drug to the active site. These data emphasize the importance of the time course of delivery of drug to the active site as an independent determinant of overall response.

Dose-Response Relationship, Drug↗
PubMed1977

Dopamine and serotonin metabolism in neuropsychiatrically disturbed children. CSF homovanillic acid and 5-hydroxyindoleacetic acid.

Lumbar cerebrospinal fluid homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and probenecid were measured in four subgroups of neuropsychiatrically disturbed children and a contrast group of pediatric patients. With the exception of a serotonin metabolite difference between autistic and nonautistic psychotic children, there were no significant differences in metabolite concentrations among autistic, nonautistic psychotic, aphasic, and cognitively and attentionally impaired groups, or between the developmentally disabled and contrast groups of children. Younger children had higher concentrations of HVA than older children. Girls had significantly lower HVA/probenecid ratios than boys, which did not appear to be related to underlying neuropsychiatric disorder. Significant probenecid-metabolite correlations indicate the importance of measuring probenecid in the cerebrospinal fluid in clinical studies.

Adolescent↗
PubMed1976

Gonorrhea in preschool- and school-aged children. Report of the prepubertal gonorrhea cooperative study group.

Single-dose antibiotic therapy was evaluated in 108 episodes of culture-confirmed, uncomplicated gonorrhea in 100 prepubertal children. There were 15 boys and 85 girls between 14 months and 14 years of age. Penicillin G procaine, 100,000 units/kg intramuscularly, was compared with amoxicillin trihydrate, 50 mg/kg orally. Probenecid, 25 mg/kg, was given simultaneously. Both drugs provided prompt bacteriological and clinical response. Multiple episodes of gonorrhea, presumably caused by reexposure, occurred in six girls. Oral and anal cultures were negative in all of 47 Costa Rican cases but were commonly positive in US children. Anal cultures yielded gonococci in 52% of girls and 25% of boys, and oral cultures were positive in 18% and 13%, respectively. In three instances, rectal cultures confirmed the diagnosis when vaginal cultures were negative. Gonorrhea should be considered in every child with vaginal or urethral discharge. Single-dose penicillin-probenecid or amoxicillin-probenecid treatment is curative.

Administration, Oral↗
PubMed1979

Biogenic amine metabolism in Tourette syndrome.

Biogenic amine metabolism in the central nervous system of 9 children with Tourette syndrome was evaluated by quantitation of their metabolites in cerebrospinal fluid by a gas chromatographic/mass spectrometric method. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were measured in CSF before and after oral administration of probenecid. Dopamine metabolism appeared defective, as both baseline and accumulated levels of HVA after probenecid were decreased. Serotonin metabolism also appeared defective in some patients with low baseline and low accumulated levels of 5-HIAA after probenecid. Taken together with other clinical features of this disease, the results suggest an underlying disorder of dopamine and serotonin metabolism in Tourette syndrome.

Biogenic Amines↗
PubMed1988

Preparation of basolateral membranes that transport p-aminohippurate from primary cultures of rabbit kidney proximal tubule cells.

The organic anion p-aminohippurate (PAH) is specifically secreted by the renal proximal tubule. The possibility was examined that the probenecid sensitive PAH transport system (which is involved in this secretory process in renal proximal tubule cells in vivo) is retained in primary cultures of rabbit kidney proximal tubule cells. Significant 3H-PAH uptake into primary cultures of proximal tubule cells was observed. After 10 min, 150 pmole PAH/mg protein had accumulated intracellularly. Given an intracellular fluid volume of 10 microliter/mg protein, the intracellular PAH concentration was estimated to be 15 microM. The initial rate of PAH uptake (when 50 microM PAH was in the uptake buffer) was inhibited 50% by 2 mM probenecid. Intact monolayers also exhibited Na+-dependent alpha methyl-D-glucoside uptake (an apical marker). Basolateral membranes were purified from primary rabbit kidney proximal tubule cell cultures. Probenecid sensitive PAH uptake into the membrane vesicles derived from the primary cultures was observed. The rate of PAH uptake was equivalent to that obtained with vesicles obtained from the rabbit renal cortex. No significant Na+-dependent D-glucose uptake into the vesicles was observed, indicating that primarily basolateral membrane vesicles had indeed been obtained.

Aminohippuric Acids↗