Metabolism in the rat of potassium nonan-5-sulphate, a symmetrical anionic surfactant

1. The metabolism of potassium nonan-5-[35S]sulphate, a symmetrical secondary alkylsulphate ester, was investigated in the rat. Oral administration of the radiolabelled ester was followed by the elimination of the majority of radioactivity in the urine. 2. Potassium nonan-5-[35S]sulphate is degraded in vivo to produce at least three radiolabelled sulphate esters. 3. The same metabolites were produced by isolated rat livers perfused with potassium nonan-5-[35S]sulphate. 4. The three radioactive metabolites were identified by combined g.l.c.-mass spectroscopy as the unchanged parent ester, nonan-1-ol-5-sulphate and nonanoate-5-sulphate. 5. The nature of the latter two metabolites indicates that potassium nonan-5-sulphate is metabolized by omega-oxidation only and, moreover, the alkylsulphate ester is metabolized only at one end of the molecule.     

Metabolism of symmetrical hexachlorobiphenyl isomers in the rat

The excretion and metabolism of four symmetrical hexachlorobiphenyl [¹⁴C] isomers 2,3,5,2′,3′,5′-hexa-; 2,3,6,2′,3′,6′-hexa-; 2,4,5,2′,4′,5′-hexa-; and 2,4,6,2′,4′,6′-hexachlorobiphenyl, have been studied in the rat. Excretion of these hexachlorobiphenyl prior to metabolism to more polar compounds was negligible. Of the four isomers studied, the three which do not have vicinal unsubstituted carbon atoms were metabolized and excreted quite slowly. One isomer, 2,3,6,2′,3′,6′-hexachlorobiphenyl, which does have vicinal unsubstituted carbon atoms, was rapidly metabolized and excreted. The results indicate that the rate of metabolism and excretion of these hexachlorobiphenyl isomers depends on the position rather than the degree of chlorine substitution on the biphenyl ring. Metabolites of these hexachlorobiphenyl isomers were isolated from rat feces and identified by comparison of their mass and NMR spectral and chromatographic properties with synthetic metabolites. The hexachlorobiphenyl metabolites showed evidence of dechlorination, chlorine shifts, and possible metabolism via the direct insertion of a hydroxyl group. The nature of the metabolites of these hexachlorobiphenyl isomers strongly supports the intermediacy of an arene oxide as the predominant mechanism of PCB metabolism. Metabolism by direct insertion of a hydroxyl group is of importance only in the absence of vicinal unsubstituted carbon atoms and is facilitated by the presence of unchlorinated meta positions.     

Modification of vulnerability to dodecylbenzenesulfonate, an anionic surfactant, by calcium in rat thymocytes

We have previously reported that cremophor EL, a nonionic surfactant, at clinical concentrations significantly decreases the cell viability of rat thymocytes with phosphatidylserine-exposed (PS-exposed) membranes under in vitro condition. It is reminiscent of a possibility that sodium dodecylbenzenesulfonate (DCBS), an anionic surfactant world-widely used for detergents, also affects the cells in the similar manner. To test the possibility, the effect of DCBS on rat thymocytes has been examined using a flow cytometer with fluorescent probes. Exposure of PS on outer surface of cell membranes was induced by A23187, a calcium ionophore to increase intracellular Ca(2+) concentration ([Ca(2+)](i)). DCBS at 1μg/mL (2.87μM) significantly decreased the viability of cells with PS-exposed membranes, but not with intact membranes. DCBS also significantly decreased the viability of cells exposed to H(2)O(2), an oxidative stress increasing the [Ca(2+)](i). On the other hand, the decrease in extracellular Ca(2+) concentration ([Ca(2+)](e)) increased the cell vulnerability to DCBS and vice versa. Intact membrane lipid bilayer and extracellular Ca(2+) are required to maintain membrane integrity. Therefore, the change of membrane property by manipulation of [Ca(2+)](i) and [Ca(2+)](e) is one of causes for the augmentation of DCBS cytotoxicity.     

Metabolism of a novel nitrosourea, tauromustine, in the rat

A novel nitrosourea, 1-(2-chloroethyl)-3-[2-(dimethylaminosulphonyl)ethyl]1-nitrosourea , tauromustine (TCNU), has been investigated for in vitro metabolism by different rat organs. Two kinds of reactions were seen, demethylation and denitrosation, both reactions required NADPH. These reactions were achieved by the liver microsomes and to a much lesser extent by lung microsomes. Induction of cytochrome P450 system with phenobarbital resulted in increased demethylation (10 times) and denitrosation (6 times) of tauromustine while induction with 3-methylcholanthrene did not have any significant effect on these reactions. Known inhibitors of different cytochrome P450 activities inhibited the demethylation and denitrosation of tauromustine to different levels. After oral administration of [14C]tauromustine a metabolic pattern similar to that observed in vitro experiments, was seen in the urine. The demethylated compound, which has alkylating cytotoxic activity, could be detected in the urine up to 8 hr after oral administration.     

Metabolism of 5-hydroxytryptophan in the isolated perfused rat lung.

The metabolism of 5-hydroxytryptophan (5-HTP) and tryptophan (TRP) in a single pass across the pulmonary circulation was studied in the isolated ventilated perfused rat lung and by high pressure liquid chromatography. The metabolism of 5-HTP was dependent on the rate of lung perfusion and the duration of infusion of 5-HTP, and was a saturable process with an apparent Km of 1.8 mM and Vmax of 0.14 mumol/g/3 min. The indoles found in the lung were 5-HTP, 5-hydroxytryptamine (5-HT) and 5-hydroxyindole acetic acid (5-HIAA); only 5-HIAA was detected in the lung effluent. The efflux of 5-HTP from the lung had two exponential components with half-lives of 0.15 and 3.65 min. After an infusion of 3H-5-HTP, the radiolabel that accumulated in lung was located mainly in the soluble fraction. An infusion of TRP resulted in the synthesis of 5-HTP, 5-HT and 5-HIAA in the lung, and 5-HTP was detected in the lung effluent. The results suggest that 5-HT can be synthesized in the intact lung from circulating TRP and 5-HTP. Since the rate of lung metabolism is low and no 5-HT is released into the lung effluent, the contribution of the lung to circulating levels of 5-HT is likely to be insignificant. Synthesis of 5-HT in intact lung suggests an intrapulmonary role for 5-HT.     

Metabolism of butalbital, 5-allyl-5-isobutylbarbituric acid, in the dog

Butalbital, 5-allyl-5-isobutylbarbituric acid, labeled in the 2-position with 14C, was administered to dogs. Ninety-two percent of the radioactivity of the dose was excreted in the urine. The drug and three major urinary metabolites were identified in the urinary excretion of the dog. The major metabolite was 5-isobutyl-5-(2,3-dihydroxypropyl)barbituric acid, which accounted for 50.2% of the dose. Smaller amounts of the unchanged drug (2.6% of the dose) and urea (8.6% of the dose) were present. 5-Allyl-5-(3-hydroxy-2-methyl-1-propyl)barbituric acid, formed by omega-hydroxylation, accounted for 10.1% of the dose; the optical rotation of the 1,3-diethyl derivative was [alpha]D20 = +10.5. Five minor and unidentified metabolities accounted for an additional 10.7% of the dose. A total of 82.2% of the dose was accounted for.     

Metabolism of denopamine, a new cardiotonic agent, in the rat and dog

The metabolism of denopamine, (R)-(-)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino] ethanol, a new, orally active, selectively inotropic cardiotonic agent, was studied in the rat and dog. Animals were given single oral doses of 5 mg/kg of denopamine labeled with 14C. Denopamine was metabolized in the rat and dog by several pathways including conjugation, side chain oxidation, and ring hydroxylation followed by O-methylation. Rats excreted the drug in the urine almost entirely as unchanged drug and its phenolic O-glucuronide whereas in the dog, the major metabolites were the phenolic O-glucuronide, the alcoholic O-glucuronide, and the phenolic O-sulfate of denopamine and the phenolic O-glucuronide of 3-methoxydenopamine. Demethylation, which has been shown to be a major metabolic pathway in man, and side chain oxidation were minor pathways in the rat and dog. Furthermore, a high degree of stereoselective resistance of the alcoholic O-glucuronide of denopamine to hydrolysis by beta-glucuronidase was observed.     

Metabolism of an anionic fluorescent dye, 1-anilino-8-naphthalene sulfonate (ANS) by rat liver microsomes

The present study was designed to examine the metabolism of 1-anilino-8-naphthalene sulfonate (ANS), an anionic compound which is transported into liver via “multispecific organic anion transporter”, with rat hepatic microsomes. TLC analysis indicated that the fluorescent metabolites were not produced to a measurable extent, which made it possible to assess the ANS metabolism by measuring the fluorescence disappearance. The metabolism of ANS was remarkably inhibited by the presence of SKF-525A as well as by the substitution of O₂ by CO gas. ANS metabolism by microsomes also required NADPH as a cofactor. These results indicated that the microsomal monooxygenase system might be mainly responsible for the ANS metabolism. The maximum velocity (V_max) and Michaelis constant (K_m) were calculated to be 4.3±0.2 nmol/min/mg protein and 42.1±2.0 μM, respectively. Assuming that 1 g of liver contains 32 mg of microsomal protein, the V_max value was extrapolated to that per g of liver (V_max). The intrinsic metabolic clearance (CL_int) under linear conditions calculated from thisin vitro metabolic study was 3.3 ml/min/g liver, being comparable with that (3.0 ml/min/g liver) calculated by analyzing the in vivo plasma disappearance curve in a previous study. Furthermore, the effects of other organic anions on the metabolism of ANS were examined. Bromophenolblue (BPB) and rose bengal (RB) competitively inhibited the metabolism of ANS, while BSP inhibited it only slightly. The inhibition constant (K_i) of BPB (6 μM) was much smaller than that of RB (200 μM). In conclusion, the microsomal monooxygenase system plays a major role in the metabolism of ANS, and other unmetabolizable organic anions (BPB and RB) compete for this metabolism.     

N,N-二甲基-1,2,3-三噻烷-5-胺草酸盐经大鼠肝微粒体的代谢

以大鼠肝微粒体为代谢模型,对沙蚕毒素类杀虫剂-易卫杀(N N-二甲基-1,2,3-三噻烷-5-胺草酸盐)进行了体外代谢观察,结果表明易卫杀经大鼠肝微粒体的代谢速率较快,其主要代谢产物有N,N-二甲基-1,2-二硫环戊烷-4胺(a,沙蚕毒素);N,N-二甲基-1,3双(甲亚磺酰基)-2-丙胺(b);N-甲基-1,2-二硫环戊烷-4-胺(c);硫磺聚合物(d)及甲基氨基丙烷(f),可能的代谢途径为:易卫杀脱掉一个硫原子变成沙蚕毒素;沙蚕毒素脱甲基生成脱甲基产物;沙蚕毒素甲基化后进一步生成N,N-二甲基-1,3-双(甲亚磺酰基)-2-丙胺。     

Metabolism and disposition of sulfluramid, a unique polyfluorinated insecticide, in the rat.

The objectives of this study were to characterize the absorption, distribution, and elimination of sulfluramid (N-ethyl perfluorooctane sulfonamide) and its major metabolite, perfluorooctane sulfonamide (DESFA), in order to assess the effect of dosage vehicle on their pharmacokinetics. In Trial 1, male and female Sprague-Dawley rats (170-240 g) were housed in Roth-type metabolism cages. Each rat received 50 mg/kg sulfluramid po, which contained 10 microCi of [14C] sulfluramid. Feces, urine, and expired air samples were collected for 72 hr post-dosing. Tissue samples also were collected at 72 hr and 14C distribution determined. Eighty percent of the radiolabel was eliminated within 72 hr, with the largest quantities of 14C recovered in expired air (56%) and feces (25%). Less radiolabel was recovered in urine (8%), and even smaller amounts in tissues (5%). The highest tissue concentrations of 14C were found in liver, kidneys, and adrenals, with significantly more radiolabel in the kidneys, gonads, and adrenals of the females than males. Male Sprague-Dawley rats (250-275 g) were used in Trials 2 and 3. In Trial 2, rats with a carotid artery cannula were given 50 mg/kg sulfluramid in a po bolus of polyethylene glycol 400 (PEG) or corn oil and blood samples were collected for 96 hr. In Trial 3, noncannulated rats were given 50 mg/kg sulfluramid po in PEG or corn oil and blood samples were collected from the caudal artery for 14 days. Blood samples were analyzed for sulfluramid and DESFA by gas chromatography.(ABSTRACT TRUNCATED AT 250 WORDS)     

Automated electronic tongue based on potentiometric sensors for the determination of a trinary anionic surfactant mixture

An automated electronic tongue consisting of an array of potentiometric sensors and an artificial neural network (ANN) has been developed to resolve mixtures of anionic surfactants. The sensor array was formed by five different flow-through sensors for anionic surfactants, based on poly(vinyl chloride) membranes having cross-sensitivity features. Feedforward multilayer neural networks were used to predict surfactant concentrations. As a great amount of information is required for the correct modelling of the sensors response, a sequential injection analysis (SIA) system was used to automatically provide it. Dodecylsulfate (DS(-)), dodecylbenzenesulfonate (DBS(-)) and alpha-alkene sulfonate (ALF(-)) formed the three-analyte study case resolved in this work. Their concentrations varied from 0.2 to 4mM for ALF(-) and DBS(-) and from 0.2 to 5mM for DS(-). Good prediction ability was obtained with correlation coefficients better than 0.933 when the obtained values were compared with those expected for a set of 16 external test samples not used for training.     

Metabolism of aminoglutethimide in the rat

The metabolism of aminoglutethimide was studied in the rat by use of the 14C-labeled compound. Following oral doses of 5 and 50 mg/kg, the drug was almost completely eliminated within 48 hr into urine and feces, mostly in the form of metabolites. In bile duct-cannulated rats, biliary excretion of radioactivity amounted to about 52% within 24 hr of an orally administered 50 mg/kg dose, with the remainder of the dose being eliminated into urine. The major urinary metabolites resulted from acetylation of the aniline moiety, hydroxylation of the glutarimide ring at positions 3 and 4, and oxidative elimination of the ethyl sidechain. The polar metabolites are accounted for by aromatic hydroxylation with subsequent sulfate conjugation and by a glutarimide ring-opened compound. In addition, a gamma-butyrolactone derivative was also identified.     

Metabolism of tetrachlorophenols in the rat

The three isomers of tetrachlorophenol were administrated intraperitoneally to rats and the urinary excretion products studied. Tetrachloro-p-hydroquinone was identified as a major metabolite of 2,3,5,6-tetrachlorophenol, constituing about 35% of the dose given. Trichloro-p-hydroquinone was identified as a minor metabolite of both 2,3,4,5- and 2,3,4,6-tetrachlorophenol. 2,3,5,6-tetrachlorophenol was eliminated within 24 h, 2,3,4,6-tetrachlorophenol within 48 h while only 60% of the given dose of 2,3,4,5-tetrachlorophenol could be recovered within 72 h.The acute toxicity of the tetrachlorophenols and tetrachloro-p-hydroquinone was studied in mice upon oral and intraperitoneal administration. 2,3,5,6-tetrachlorophenol (LD₅₀ p.o. 109 mg · kg^–1) was the most toxic compound followed y 2,3,4,6- and 2,3,4,5-tetrachlorophenol (LD₅₀ p.o. 131 and 400 mg · kg^–1, respectively). Tetrachloro-p-hydroquinone proved to have low oral toxicity (LD₅₀ p.o. 500 mg · kg^–1) but was more toxic than the tetrachlorophenols when administered intraperitoneally. The oral LD₅₀ for pentachlorophenol, under identical experimental conditions, was found to be 74 mg · kg^–1.

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Zusammenfassung Die drei Isomeren von Tetrachlorphenol wurden an Ratten intraperitoneal verabreicht und die Ausscheidungsprodukte in Harn untersucht. Tetrachlor-p-hydrochinon erwies sich als Hauptmetabolit von 2,3,5,6-Tetrachlorphenol, entsprechend etwa 35% der zugeführten Menge. Bei sowohl 2,3,4,5-als auch 2,3,4,6-Tetrachlorphenol wurde Trichlor-p-hydrochinon als Metabolit identifiziert, jedoch in geringer Menge. Das 2,3,5,6-Tetrachlorphenol wurde innerhalb von 24 Std und das 2,3,4,6-Tetrachlorphenol innerhalb von 48 Std eliminiert, während bei 2,3,4,5-Tetrachlorphenol innerhalb von 72 Std nur 60% der gegebenen Menge erfaßt werden konnte.Die akute Toxizität von Tetrachlorphenolen und Tetrachlor-p-hydrochinon wurden an Mäusen oral sowie intraperitoneal studiert. 2,3,5,6-Tetrachlorphenol erwies sich als die toxischste der Substanzen (LD₅₀ p.o. 109 mg · kg^–1), gefolgt von 2,3,4,6- und 2,3,4,5-Tetrachlorphenol (LD₅₀ p.o. 131 mg · kg^–1 und 400 mg · kg^–1). Tetrachlor-p-hydrochinon zeigte nur geringe Toxizität, wenn oral verabreicht (LD₅₀ 500 mg · kg^–1), war aber toxischer als die Tetrachlorphenole, wenn intraperitoneal gegeben.

     

Metabolism of a monoterpene ketone, R-(+)-pulegone--a hepatotoxin in rat

1. R-(+)-Pulegone was administered orally to rats and the urinary metabolites were investigated. Six metabolites were isolated and purified using column and thin layer chromatographic techniques. Metabolites were identified by i.r., n.m.r. and mass spectral analyses. 2. The neutral metabolites isolated from urine of rats treated with pulegone (I) were: pulegone (II), 2-hydroxy-2(1'-hydroxy-1'-methylethyl)-5-methylcyclohexanone (III), 3,6-dimethyl-7a-hydroxy-5,6,7,7a-tetrahydro-2(4H)-benzofuranone (V) and menthofuran (VII). Metabolites II and III were also excreted in conjugated form. 3. Acidic metabolites isolated from urine of rats treated with pulegone (I) were: 5-methyl-2(1'-methyl-1'-carboxyethylidene)cyclohexanone (IV) and 5-methyl-5-hydroxy-2(1'hydroxy-1'-carboxyethyl)cyclohexanone (VI).     

5-HT1A receptors activate a potassium conductance in rat ventromedial hypothalamic neurones.

The extracellularly recorded firing rate of rat ventromedial hypothalamic neurones in vitro was inhibited by 5-hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone, 2-methyl-5-HT was relatively ineffective. At 1 microM, spiperone and cyanopindolol antagonised the 5-CT induced inhibition, MDL 72222 (10 microM) and ketanserin (1 microM) did not. Intracellular recordings with voltage-clamp revealed that 5-HT and 5-CT evoked a tetrodotoxin-resistant outward current with a reversal potential of ca. -100 mV. 5-HT1A receptors likely activate a potassium conductance on these neurones.