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PubMedDate not supplied

Protection from 1-cyano-3,4-epithiobutane nephrotoxicity by aminooxyacetic acid and effect on xenobiotic-metabolizing enzymes in male Fischer 344 rats.

1-Cyano-3,4-epithiobutane (CEB), a naturally occurring nitrile derived from cruciferous plants, causes nephrotoxicity and increased renal glutathione (GSH) concentration in male F-344 rats. This CEB-induced nephrotoxicity is dependent on GSH conjugation and bioactivation. The objectives of the present study were to investigate the effect of CEB on several xenobiotic-metabolizing enzymes and to evaluate the effect of modulators of GSH transport and metabolism on CEB-induced nephrotoxicity and GSH concentration. Animals received 125 mg kg-1 CEB alone or following pretreatment with one of three selective inhibitors of GSH metabolism: acivicin, probenecid or aminooxyacetic acid. There were no significant alterations in epoxide hydrolase (EH), P-450, ethoxyresorufin O-deethylase (EROD) or pentoxyresorufin O-depentylase (PROD) enzyme activity, but renal glutamyl cysteine synthetase (GCS) activity was decreased at 12 and 24 h, as was renal glutathione S-transferase 4 h after CEB administration. Renal ECOD activity was also diminished at 24 h and at 12 and 24 h in liver. Aminooxyacetic acid (AOAA) abrogated the nephrotoxicity, the renal GSH-enhancing effect, and decreased GCS of CEB alone. These findings provide further evidence for the importance of GSH conjugation as a significant pathway in CEB metabolism and the role of a reactive thiol in nephrotoxicity and altered renal GSH.

7-Alkoxycoumarin O-Dealkylase↗
PubMedDate not supplied

Identification of the 1-cyano-3,4-epithiobutane-derived urinary mercapturic acid N-acetyl-S-(4-cyano-2-thio-1-butyl)-cysteine in male Fischer 344 rats.

1-Cyano-3,4-epithiobutane (CEB), a naturally occurring nitrile derived from cruciferous plants, causes nephrotoxicity in male Fischer 344 rats. Nephrotoxicity induced by CEB is dependent on glutathione (GSH) conjugation and bioactivation. Conjugation with GSH and subsequent metabolism leads to the formation of specific urinary metabolites. The objectives of the present study were to identify CEB-derived urinary metabolites and quantify urinary non-protein thiols and thioethers in male Fischer 344 rats. Animals received 125 mg kg(-1) of CEB alone or following pretreatment with one of three selective inhibitors of GSH metabolism: acivicin, probenecid or aminooxyacetic acid. Total non-protein urinary thiol and urinary thioether concentrations were elevated in all treated groups at 12 and 24 h; however, elevations in non-protein thiols were not significantly greater in rats administered CEB alone as compared to negative controls. A single predominant urinary metabolite was identified as the CEB-derived mercapturic acid N-acetyl-S-(4-cyano-thio-1-butyl)-cysteine. Evidence for other CEB-derived metabolites was also demonstrated. These findings represent the identification of a unique compound and provide further evidence for the importance of GSH conjugation as a significant pathway in CEB metabolism.

Acetylcysteine↗
PubMedDate not supplied

Postsecretory reabsorption of urate in man.

These results are consistent with a model for renal tubular transport of urate in which there is reabsorption of both filtered and secreted urate. Urate secretion greatly exceeds total urate excretion, and most secreted urate is reabsorbed. At least a portion of urate reabsorption occurs at a site distal to or coextensive with the urate secretory site. There appear to be at least two distinct reabsorptive mechanisms for urate. The results of the flow rate and vasopressin studies are consistent with the hypothesis that urate reabsorption occurs in both the distal and the proximal tubule in man. The distal reabsorptive site appears to be quite small. It may be passive since it does not appear to be inhibited by uricosuric drugs. This reabsorptive site may account for less than 15% of total urate reabsorption. Both volume expansion and probenecid may inhibit urate absorption only in the proximal tubule. Thus reabsorption in the proximal tubule coud account for more than 90% of total urate reabsorption. Reabsorption at the postulated collecting duct reabsorptive site appears to be too small in magnitude to account for all reabsorptions of secreted urate. This could be explained if the reabsorptive site in the proximal tubule is coextensive with or distal to the secretory site. Alternatively, there might be two reabsorptive sites in the proximal tubule: a presecretory site accounting for the reabsorption of most filtered urate, and a site either coextensive or distal to the secretory site accounting for a major component of reabsorption of secreted urate. Finally urate reabsorption would also take place in the collecting duct, perhaps at a passive, flow-dependent site.

Aspirin↗
PubMed1994

Treatment of Lyme arthritis.

OBJECTIVE: To test treatment regimens for Lyme arthritis. METHODS: Patients were randomly assigned to treatment with doxycycline or amoxicillin plus probenecid for 30 days. Patients who had persistent arthritis for at least 3 months after treatment with oral antibiotics or parenteral penicillin were given intravenous ceftriaxone for 2 weeks. RESULTS: Eighteen of the 20 patients treated with doxycycline and 16 of the 18 patients who completed the amoxicillin regimen had resolution of the arthritis within 1-3 months after study entry. However, neuroborreliosis later developed in 5 patients, 4 of whom had received the amoxicillin regimen. Of 16 patients (2 from the oral antibiotic study and 14 additional patients) who had persistent arthritis despite previous oral antibiotics or parenteral penicillin, none had resolution of the arthritis within 3 months after ceftriaxone therapy. The HLA-DR4 specificity and OspA reactivity were associated with a lack of response. CONCLUSION: Lyme arthritis can usually be treated successfully with oral antibiotics, but patients may still develop neuroborreliosis. Patients with certain genetic and immune markers may have persistent arthritis despite treatment with oral or intravenous antibiotics.

Adolescent↗
PubMedDate not supplied

Pharmacokinetics, metabolism and renal excretion of sulfatroxazole and its 5-hydroxy- and N4-acetyl-metabolites in man.

Hydroxylation is the predominant pathway of metabolism for sulfatroxazole in the body, accounting for 70 per cent of the dose. Fifteen per cent of the dose is acetylated unimodally and 10 per cent is excreted unchanged. The half-lives of sulfatroxazole and its metabolites 5-hydroxysulfatroxazole and N4-acetylsulfatroxazole are approximately 22 h after administration of sulfatroxazole. N4-acetylsulfatroxazole, taken as parent drug, is eliminated by renal excretion (92 per cent of the dose). The initial elimination half-life of N4-acetylsulfatroxazole is 4.5 h, which later increases to 70 h as the result of the acetylation-deacetylation equilibrium. Probenecid inhibits the renal excretion of the metabolites 5-hydroxy- and N4-acetylsulfatroxazole. Inhibition of the N4-acetyl metabolite favours the deacetylation, which results in an increase of the T 1/2 of sulfatroxazole from 20 to 30 h. The protein binding value of sulfatroxazole is 84 per cent, that of N4-acetylsulfatroxazole is 37 per cent. Sulfatroxazole is excreted renally by passive processes, while the metabolites are excreted by both passive and active processes.

Acetylation↗
PubMed2006

Apparent active transport of MDMA is not mediated by P-glycoprotein: a comparison with MDCK and Caco-2 monolayers.

Amphetamines and their methylenedioxy derivatives generically display similar behavioral, physiologic and toxic effects. Inconsistent pharmacokinetic and toxicity data for methylenedioxymethamphetamine (MDMA) may suggest that active drug transporters are interacting with these compounds, and thus altering drug absorption and tissue distribution. In vitro models of CNS accumulation and intestinal drug transport were used to assess efflux transport of MDMA. Madin-Darby kidney cell epithelial (MDCK) monolayers displayed a 4-fold increase in accumulation in the basolateral to apical orientation relative to the apical to basolateral orientation, although no differential accumulation was noted between MDCK-WT and MDCK-MDR1 monolayers. Caco-2 monolayers demonstrated an approximate 2-fold increase in accumulation of MDMA. Exposure of various inhibitors of active drug transporters demonstrated mixed results; ritonavir, progesterone and indomethacin produced an approximately 50% reduction of MDMA transport, while verapamil, MK-571 and probenecid had no effect. Based on these data, it is concluded that MDMA efflux is mediated via the activity of a transporter distinct from P-glycoprotein. The possible inhibitory effects of amphetamines on rhodamine-123 transport were also assessed. MDMA, methylenedioxyamphetamine, amphetamine and methamphetamine, at physiologically relevant concentrations, did not significantly alter the transport of rhodamine-123 in Caco-2 monolayers or the LS180 cell line, suggesting that these compounds do not alter the function of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Transport of methotrexate into LNCaP human prostate cancer cells.

Uptake of methotrexate into the LNCaP human prostate cancer cells was linear for the first 60 min. The initial rate of methotrexate uptake was highest at extracellular pH 4.5 and decreased markedly until pH 7.0 to 8.0. Transport of methotrexate into LNCaP cells showed two components, one saturable -K(m) = 0.13 +/- 0.06 microM and V(max) = 1.20 +/- 0.16 pmol x 45 min(-1) x mg(-1) protein at low concentrations and the other apparently not saturable up to 10 microM. Uptake of methotrexate was inhibited by structural analogs with the K(i) values being 6.53, 12.4, and 85.6 microM for 5-formyltetrahydrofolate, 5-methyltetrahydrofolate, and folic acid, respectively. Uptake of methotrexate into LNCaP cells was not inhibited by the energy poisons in contrast to methotrexate uptake into PC-3 prostate cancer cells. Uptake was inhibited by increasing concentrations of sulfate and phosphate ions and by the organic anions probenecid and DIDS, suggesting that methotrexate may be transported by an anion-exchange mechanism. These results show that methotrexate is transported into LNCaP prostate cancer cells by a carrier-mediated process.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1975

Ticarcillin vs carbenicillin: clinical pharmacokinetics.

The pharmacokinetic characteristics of ticarcillin, a semisynthetic penicillin more active than carbenicillin against Pseudomonas, were compared to those of carbenicillin in 12 healthy volunteers. Following an intravenous infusion of 2 gm in 5 min, there was a lower average serum level for ticarcillin (218 mug/ml) than for carbenicillin (301 mug/ml), but after 2 hr the differences were not significant. The biologic half-life of ticarcillin was slightly longer than that of carbenicillin (72 and 65 min, P smaller than 0.01) and its volume of distribution was larger (15.7 and 12.3 l, P smaller than 0.01). Eighty-six per cent of the dose of ticarcillin and 99 percent of the dose of carbenicillin was recovered in the urine in 24 hr. Similar but much less marked blood level differences were noted with 2 gm, 30-min infusions. An intravenous infusion of 1 gm/hr gave average steady-state blood levels of about 124 mug/ml for both antibiotics. Probenecid, administered 1 hr before the infusion, caused significant and similar increases in blood levels, half-lives, and volumes of distribution of the 2 antibiotics. Protein binding in 100 percent human serum was 50 percent and 65 percent for carbenicillin and ticarcillin, respectively. These relatively small but definite differences in the pharmacokinetics of ticarcillin and carbenicillin are not likely to be of clinical significance.

Carbenicillin↗
PubMed1975

Fenfluramine in man: hypophagia associated with diminished serotonin turnover.

A double-blind trial of orally administered fenfluramine was conducted in 7 non-obese adults with various neurological disorders. Caloric intake and body weight fell significantly after 8 days of treatment although there was no definite change in appetite ratings. Average central turnover of serotonin, as estimated by the cerebrospinal fluid (CSF) accumulation of 5-hydroxyindoleacetic acid (5-HIAA) during probenecid loading, decreased by 66%. No significant change in homovanillic acid, the major dopamine product, was apparent. The results support the contention that the effect of fenfluramine on human dietary intake may be mediated by alterations in serotonergic rather than dopaminergic mechanisms.

Adult↗
PubMed2002

Single-cell image analysis to assess ABC-transporter-mediated efflux in highly purified hematopoietic progenitors.

BACKGROUND: Normal and malignant hematopoietic stem cells are characterized by their capacity to actively extrude fluorescent dyes. The contribution of different ATP-binding cassette (ABC) transporters to this phenomenon is largely unknown due to the small stem cell numbers limiting the use of standard methods to assess functional efflux. METHODS: We used epifluorescence microscopy (EFM) in combination with single-cell image analysis to study ABC-transporter-mediated efflux in highly purified, viable, CD34+CD38- cells sorted on an adhesive biolayer. P-glycoprotein and multidrug-resistant protein (MRP)-mediated efflux were quantitated using fluorescent substrates (rhodamine-123 and calcein acetoxymethyl ester [calcein-AM]) and specific inhibitors (verapamil and probenecid, respectively). RESULTS: The feasibility, sensitivity, and reproducibility of rhodamine-123 efflux quantitation using single-cell EFM was shown in cell lines and compared with standard flow cytometric assessment. P-glycoprotein-mediated transport was higher in CD34+CD38- cells than in more differentiated progenitors (mean efflux index = 2.24 +/- 0.35 and 1.14 +/- 0.11, respectively; P = 0.01). P-glycoprotein-mediated transport was the main determinant of the rhodamine "dull" phenotype of these cells. In addition, significant MRP-mediated efflux was demonstrated in CD34+CD38- and CD38+ cells (mean efflux index = 1.42 +/- 0.19 and 1.28 +/- 0.18, respectively). CONCLUSION: The described method is a valuable tool for assessing ABC-transporter-mediated efflux in highly purified single cells. Both P-glycoprotein and MRP-mediated efflux are present in human CD34+CD38- hematopoietic stem cells.

ADP-ribosyl Cyclase↗
PubMedDate not supplied

Hypouricemia and hyperuricosuria as expressions of renal tubular damage in primary biliary cirrhosis.

Renal tubular damage, in particular, renal tubular acidosis is associated with primary biliary cirrhosis (PBC), but hypouricemia has not been described. We studied four patients with PBC whose serum uric acid levels were 1.4 to 1.8 mg per dl, and compared their renal and liver functions with those of 11 patients with PBC whose serum uric acid levels were normal. In the patients with PBC and hypouricemia, uric acid clearance (Cua) and the ratio of Cua and creatinine clearance (Cua/Ccr) were high enough to cause hypouricemia. Elevated Cua/Ccr was suppressed by administration of pyrazinamide, a blocker of tubular secretion of uric acid, but was not affected by probenecid; the effects of drugs on Cua/Ccr were similar to those reported in Wilson's disease. Elevation in Cua/Ccr was associated with increased serum bilirubin and urinary copper excretion. These observations indicate that hypouricemia and hyperuricosuria, which may be caused by defective postsecretory reabsorption of uric acid, are additional indicators of renal tubular damage in PBC.

Acidosis, Renal Tubular↗
PubMed1992

Identification and modulation of a voltage-dependent anion channel in the plasma membrane of guard cells by high-affinity ligands.

Guard cell anion channels (GCAC1) catalyze the release of anions across the plasma membrane during regulated volume decrease and also seem to be involved in the targeting of the plant growth hormones auxins. We have analyzed the modulation and inhibition of these voltage-dependent anion channels by different anion channel blockers. Ethacrynic acid, a structural correlate of an auxin, caused a shift in activation potential and simultaneously a transient increase in the peak current amplitude, whereas other blockers shifted and blocked the voltage-dependent activity of the channel. Comparison of dose-response curves for shift and block imposed by the inhibitor, indicate two different sites within the channel which interact with the ligand. The capability to inhibit GCAC1 increases in a dose-dependent manner in the sequence: probenecid less than A-9-C less than ethacrynic acid less than niflumic acid less than IAA-94 less than NPPB. All inhibitors reversibly blocked the anion channel from the extracellular side. Channel block on the level of single anion channels is characterized by a reduction of long open transitions into flickering bursts, indicating an interaction with the open mouth of the channel. IAA-23, a structural analog of IAA-94, was used to enrich ligand-binding polypeptides from the plasma membrane of guard cells by IAA-23 affinity chromatography. From this protein fraction a 60 kDa polypeptide crossreacted specifically with polyclonal antibodies raised against anion channels isolated from kidney membranes. In contrast to guard cells, mesophyll plasma membranes were deficient in voltage-dependent anion channels and lacked crossreactivity with the antibody.

Benzoates↗
PubMed1998

Characterization of cyclic AMP efflux from swine adipocytes in vitro.

OBJECTIVE: A variety of cell types transport cyclic AMP (cAMP) to the extracellular fluid; the purpose of this study was to determine if and how this process occurs in adipocytes. RESEARCH METHODS AND PROCEDURES: Adipocytes were isolated from 3-month-old swine and incubated with stimulators of adenylate cyclase for 2 to 120 minutes to promote cAMP synthesis and efflux. Efflux was characterized in the presence of agents that inhibit ATP production, anion transport, intracellular cAMP metabolism, and extracellular cAMP metabolism. Extracellular cAMP was measured by enzyme immunoassay, then corrected for cell lysis by measuring lactate dehydrogenase release. RESULTS: cAMP efflux averaged 24.7 fmol/min/cm2 adipocyte surface area, was linear for 2 hours, and was proportional to adipocyte surface area (r=0.94, p<0.05). Efflux was reduced by approximately 35% in cells incubated with 1 microM antimycin, an inhibitor of ATP synthesis (p<0.05), and by approximately 55% in cells incubated with 2 mM probenecid, an anion-specific transport blocker (p<0.05). Extracellular cAMP levels more than doubled by the addition of 1 microM 1,3-dipropyl-8-p-sulfophenylxanthine, a purported inhibitor of extracellular phosphodiesterase. DISCUSSION: Our data demonstrate that cAMP is transported from swine adipocytes by an energy-dependent anion transporter and can be metabolized extracellularly. Future studies will evaluate extracellular cAMP as a potential source of extracellular adenosine, a potent inhibitor of adipocyte lipolysis.

Adipocytes↗
PubMed1989

Renal handling of 2-methyl-4-chlorophenoxyacetic acid (MCPA) in rats.

Following i.p. administration of various doses of 2-methyl-4-chlorophenoxyacetic acid (MCPA), ca. 50% is excreted during a 5-h diuresis experiment. After i.p. administration of MCPA, virtually no distribution occurs (Vrel = 18% of the body weight). Renal excretion of MCPA can be accelerated by inhibition of its renal tubular reabsorption. The distinct inhibition of renal excretion of MCPA by simultaneous administration of probenecid or p-aminohippurate (PAH) indicates the active tubular transport of MCPA; this transport process can be stimulated by treatment of rats with triiodothyronine. Active tubular transport of MCPA was confirmed by measurement of MCPA accumulation in renal cortical slices, both under aerobic and anaerobic conditions. Accumulation of MCPA under anaerobic conditions indicates an additional passive uptake and binding of MCPA in kidney tissue in accordance with the high degree of binding to plasma albumin (85%).

2-Methyl-4-chlorophenoxyacetic Acid↗
PubMed1992

Renal excretion of perfluorooctanoic acid in male rats: inhibitory effect of testosterone.

There is a marked sex difference in the whole-body elimination of perfluorooctanoic acid (PFOA) in rats, with females excreting the perfluorinated acid much more rapidly (half life [t1/2] less than 1 day) than males (t1/2 = 15 days). Our objective was to determine if androgens or estrogens are involved in causing this sex difference in PFOA elimination. Castration of males greatly increased the elimination of [1-14C]PFOA (9.4 mumol/kg, i.p.) in urine, demonstrating that a factor produced by the testis was responsible for the slow elimination of PFOA in male rats. Castration plus 17 beta-estradiol had no further effect on PFOA elimination whereas castration plus testosterone replacement at the physiologic level reduced PFOA elimination to the same level as rats with intact testes. Thus, in male rats, testosterone exerts an inhibitory effect on renal excretion of PFOA. In female rats, neither ovariectomy nor ovariectomy plus testosterone affected the PFOA urinary elimination, demonstrating that the inhibitory effect of testosterone on PFOA renal excretion is a male-specific response. Probenecid decreased the high rate of PFOA renal excretion in castrated males but had no effect on male rats with intact testes. We conclude that testosterone is a key determinant of the sex difference in PFOA elimination in rats.

Alpha-Globulins↗
PubMed1998

Expression of multidrug resistance-associated protein (MRP) in brain microvessel endothelial cells.

Multidrug resistance-associated protein (MRP) is a recently identified drug efflux transport system that actively transports organic acids and selected glucuronide or glutathione conjugates out of the cell. The current study presents, for the first time, both functional and biochemical data demonstrating the presence of MRP in the brain microvessel endothelial cells that form the blood-brain barrier (BBB). Using known MRP inhibitors, such as indomethacin and probenecid, fluorescein accumulation in primary cultured bovine brain microvessel endothelial cell (BBMEC) monolayers was significantly enhanced compared to control. The specificity of the MRP inhibitors on cellular fluorescein accumulation was confirmed using both MRP positive (Panc-1) and MRP negative (KBv) cell lines. Furthermore, western blot analysis using a specific antibody for MRP (MRPm6) and RT-PCR studies using a complementary sequence probe for human MRP demonstrate the expression of MRP in BBMEC. Previous studies have demonstrated the significance of the P-glycoprotein drug efflux transporter in the BBB. Given its function as a drug efflux transport system, it is anticipated that MRP in the BBB will also have an important role in limiting the exposure of the brain to many endogenous and exogenous compounds, including both toxic and therapeutic agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Multidrug resistance P-glycoprotein is not involved in cholesterol esterification.

The aim of the present paper is to reinvestigate the role of multidrug resistance P-glycoprotein MDR1 and MDR-associated protein (MRP1) in cholesterol esterification using well-characterized inhibitors. Using specific substrate efflux assay, we show that GF120918 (0.2 microM) and probenecid (5 mM) were specific inhibitors of MDR1 and MRP1, respectively. In HepG2 cells, neither of them affect the esterification of cholesterol derived from the uptake of cholesterol-rich lipoprotein, while both verapamil (100 microM) and progesterone (100 microM) were able to inhibit cholesterol esterification. Similar results were obtained with verapamil, progesterone, and GF120918 in the MDR1-overexpressing cells MCF7/ADR. The capacity of progesterone to reduce cholesterol esterification is not correlated with its ability to inhibit MDR1 but is rather due to direct inhibition of acyl-CoA:cholesterol acyltransferase (ACAT). We conclude that the esterification of cholesterol is not correlated with MDR1 or MRP1 activity, thus excluding their role in the intracellular transport of endocytosis-derived cholesterol.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Fluorescent indicators give biased estimates of intracellular free calcium change in aggregating platelets: implication for studies with human von Willebrand factor.

The ratiometric fluorescent indicators Fura-2 and Indo-1 are considered optimal probes for monitoring intracellular free calcium concentration ([Ca2+]i). Unique problems arise, however, in studying [Ca2+]i changes induced in platelets by von Willebrand factor (vWF). Binding of native multimeric vWF causes extensive platelet aggregation, and is reported to evoke a gradual [Ca2+]i increase. the present investigation examined the reliability of platelet [Ca2+]i measurements in these circumstances. Ristocetin-mediated binding of vWF to human platelets promoted a slow rise in Fura-2 fluorescence ratio. Fura-2 extrusion contributed substantially to this rise, unless blocked by probenecid. Despite this precaution, the platelets were invariably contaminated slightly with extracellular indicator. As aggregation progressively reduced the number of platelets in the spectrofluorometer beam, through settling of the larger aggregates, such extracellular Fura-2 contributed proportionately more to the observed fluorescence. This extraneous signal accounted completely for the fluorescence ratio increase, and apparent [Ca2+]i rise, in response to native multimeric vWF. The same problem arose with Indo-1, whereas the single wavelength indicator Fluo-3 showed the opposite pattern of apparent [Ca2+]i changes. Thus, none of these indicators provides reliable data on [Ca2+]i signals in aggregating platelets. Use of a dimeric form of vWF eliminated the problem of platelet aggregates settling out of suspension, but also virtually abolished the [Ca2+]i increase. These observations may explain some of the inconsistencies among previous investigations of vWF-induced calcium signaling. Moreover, similar problems may arise in studies with other adhesive proteins.

Alkylation↗