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1.
The excretion patterns and tissue residues were determined after single and repeated oral dosing of rats with triazophos-14C Within 4 days after a single oral dose 76.3 % of the 14C was excreted in the urine and 21.0% in the faeces. After daily application for 12 days 69.5–83.4% of the label was eliminated in urine and 30.9–18.1 % in the faeces. Following prolonged application, however, elimination is distinctly slower. Distribution of radioactive residues in organs and tissue in both test series showed no appreciable or critical concentrations of radioactivity, with the exception of the gastrointestinal tract (contents and walls). Unchanged triazophos and l-phenyl-1,2,4-triazol-3-ol-3-14C were excreted in the faeces. Renewed release of other metabolites into the gastrointestinal tract apparently does not take place. The following metabolites are detected in the urine: urea-14C (approx. 85% of the radioactivity excreted with the urine); and three compounds as conjugates with glucuronic acid, i.e. 1-phenyl-l,2,4-triazol-3-ol-3-14C (approx. 3%), l-phenylsemicarbazide-3-14C (approx. 5%), and semicarbazide-14C (approx. 5%). Two further metabolites, so far unidentified, occurred in small quantities.  相似文献   

2.
Upon single oral administration to rats, the mono-, di- and tri-glucose conjugates of [14C]-3-phenoxybenzyl alcohol ( I ) or the mono-glucose conjugate of [14C]-3-phenoxybenzoic acid ( II ) were rapidly hydrolysed and extensively eliminated in the urine mostly as the sulphate conjugate of 3-(4-hydroxyphenoxy)benzoic acid ( X ). The faecal elimination was a minor route, whereas the biliary excretion was about 42% of the dose and the glucuronide conjugates of I , II and X were common major metabolites. The biliary glucuronides were cleaved in the small intestine to the respective aglycones, which were reabsorbed, metabolised further, and excreted in the urine as the sulphate conjugate of X . Although small amounts of the mono-, di-and tri-glucosides were found in the 0.5-h blood and liver samples following oral administration of the tri-glucoside of I , they were not detected in the urine, bile or faeces. Similarly the sulphate conjugate was one of the major urinary metabolites of germ-free rats, dosed with the 14C-glucosides via the oral or the intraperitoneal route, although they were excreted unchanged in certain amounts in the urine and faeces. The glucose conjugates were cleaved in vitro by gut microflora and in various rat tissues, including blood, liver, small intestine and small intestinal mucosa. The tissue enzymes showed a different substrate specificity in hydrolysis of the glucosides. However, they were not cleaved in gastric juice, bile, pancreatic juice or urine.  相似文献   

3.
Rats and chickens were each given a single oral dose (10 or 100 mg/kg body wt) of 1,1,1-trifluoro-N-[2-methyl-4-(phenylsulfonyl)phenyl-14C(U)]methanesulfonamide ([14C]perfluidone). Depending on the size of the dose, from 8.4 to 36.2% of the [14C] was eliminated in the urine and from 36.4 to 85.4% was eliminated in the feces within 48 hr after dosing. Less than 1% of the [14C] given to laying hens as [14C]perfluidone was present in the eggs produced during the first 96 hr after dosing. The percentage of the administered [14C] that remained in these animals (body with G.I. tract and contents removed) varied from 0.34 (96 hr after dosing) to 1.68% (48 hr after dosing). 14C-labeled compunds in the urine and feces from the rats and chickens were purified by solvent extraction, column chromatography, and gas-liquid chromatography, and then identified by infrared and mass spectrometry. The parent compound was the major 14C-labeled component in the urine and feces of both animals. 1,1,1-Trifluoro-N-[2-methyl-4-(3-hydroxyphenylsulfonyl)phenyl]methanesulfonamide was present in the feces of both animals. The proposed structures of other metabolites were 1,1,1-trifluoro-N-hydroxy-N-[2-methyl-4-(phenylsulfonyl)phenyl]methanesulfonamide (rat urine) and 1,1,1-trifluoro-N-{2-methyl-4-[(methylsulfonyl)-phenylsulfonyl]phenyl}methanesulfonamide (chicken urine).  相似文献   

4.
The disposition of the pyrethroid insecticide cypermethrin, (RS)-a-cyano-3-phenoxybenzyl (1RS)-cis, trans-3-(2,2-dichlorovinly)-2, 2-dimethylcyclopropane-carboxylate, has been studied in male and female rats following a single toxic oral dose (200mg kg−1) of two radiolabelled forms ([14C-benzyl] and [14C-cyclopropyl]) of the insecticide. The bioaccumulation and elimination of 14C-benzyl-labelled cypermethrin, following repeated administration at a sub-toxic dose (2mg kg−1), has also been studied in male and female rats. Although, at the toxic dose, radioactivity from the two radiolabelled forms was rapidly eliminated in urine and faeces, the increased excretion in the faeces, over that for low doses, was evidence that absorption was incomplete. The major pathways of metabolism involved cleavage of the ester bond, with subsequent hydroxylation and glucuronidation of the cyclopropyl acid moieties, together with hydroxylation and sulphation of the 3-phenoxybenzyl moiety. The absence of sex- or dose-dependent changes was reflected by the constant proportions of these metabolites found in the urine. Constant levels of radioactivity in tissues were achieved rapidly, generally within the first week of repeated administration. Elimination was rapid on the cessation of dosing, although less rapid from the fat and skin. The material in the fat was mainly the cis-isomers of cypermethrin, which were eliminated with a mean half-life of 18.2 days, compared with 3.4 days for the trans-isomers.  相似文献   

5.
The metabolism of the pyrethroid insecticide α-cyano-3-phenoxybenzyl 2,2,3,3-tetramethylcyclopropanecarboxylate (WL 41706) has been studied in rats using two forms of 14C-labelling (benzyl- and cyclopropyl-). Excretion of benzyl?14C was rapid, 57% of the administered dose being eliminated in the urine 48 h after treatment and 40% in the faeces. No significant sex difference was observed. The amount of radioactivity excreted via expired gases was 0.005% of the administered dose and less than 1.5% of the dose remained in the animals 8 days after treatment. The mean percentage recovery of administered dose was 104% for male rats and 97% for female rats. Urinary and faecal metabolites from these rats, and from rats dosed similarly with [cyclopropyl?14C]-WL 41706 were studied. The rapid metabolism of WL 41706 is due to efficient cleavage of the ester bond by rats in vivo to afford 2,2,3,3-tetramethylcyclopropanecarboxylic acid (partly as glucuronide) and the 3-phenoxybenzyl moiety. Before this cleavage occurs, however, about half of the intake suffers aryl hydroxylation giving the α-cyano-3-(4-hydroxyphenoxy)benzyl ester, part of which is excreted in the bile as a conjugate(s) and part of which is cleaved and eliminated as the O-sulphate of 3-(4-hydroxyphenoxy)benzoic acid and the glucuronide of 2,2,3,3-tetramethylcyclopropanecarboxylic acid. A minor amount of hydroxylation occurs at a trans-methyl group on the cyclopropane acid moiety. The metabolism of WL 41706 by rat liver occurs mainly in the microsomes and mainly via oxidative processes.  相似文献   

6.
Metabolism in mice of the separated cis- and trans-isomers of the pyrethroid insecticide cypermethrin (NRDC 149), (RS)-α-cyano-3-phenoxybenzyl (1RS)-cis, trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate, was investigated in each case with preparations that were 14C-labelled in the benzyl and cyclopropyl moieties. Radioactivity from the trans-isomer was mainly excreted in the urine and that from the cis-isomer in the faeces. Elimination of both isomers was rapid except for a small portion (approximately 2%) of the cis-isomer which was released from the fat with a half-life of approximately 13 days. Metabolism of cypermethrin occurred mainly by ester cleavage and elimination of the cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethyl- cyclopropanecarboxylic acid moieties as glucuronide conjugates. The α-cyano-3-phenoxybenzyl alcohol released by ester cleavage was mainly converted to 3-phenoxy-benzoic acid which was partly eliminated unchanged, partly conjugated with aminoacids (mainly taurine) and glucuronic acid, and partly oxidised to 3-(4-hydroxyphenoxy) benzoic acid which was excreted as the sulphate conjugate. Metabolites retaining the ester linkage were formed by hydroxylation at various sites in the molecule with more hydroxylation of the cis- than of the trans-isomer occurring.  相似文献   

7.
A rat, given a single oral dose of [14C] cymoxanil, 1-(2-cyano-2-methoxyimino-[2-14C]-acetyl)-3-ethylurea, eliminated 91% of the radioactivity within 72 h. The urine contained 71%, the faeces 11%, and the expired air about 7% of the radiolabel; no 14C residue was found in the internal organs. Greater than 70% of the radioactivity in the urine was identified. The major metabolite was characterised as glycine, both free and conjugated, as hippuric acid and phenylaceturic acid [N-(phenylacetyl)-glycine], and probably in the form of polypeptides of low molecular weight. The other metabolites identified included 2-cyano-2-methoxyiminoacetic acid, 2-cyano-2-hydroxyiminoacetic acid and 1-ethylimidazolidine-2, 4, 5-trione. The minor metabolites included succinic acid and 2-oxoglutaric acid which indicated reincorporation of metabolic 14C. Cymoxanil, as such, was not detected in the urine.  相似文献   

8.
The metabolism of benodanil (2-iodobenzanilide) was studied in rats following an oral dose of 150 mg benodanil kg?1 body weight. The major 24-h urinary metabolite was found to be the 4′-hydroxy derivative, both free (≈ 5%) and as the glucuronide (≈ 4%) and sulphate (≈ 4%) conjugates. Over a 6-day period, about 16% of the administered dose was excreted in the urine and about 80% in the faeces. After dosing with [14C]- benodanil, blood radioactivity levels were highest 30 min after dosing, with small broader peaks at 4 and 7 h, while biliary activity levels rose slowly to a maximum about 10–12 h after the dose, some 16% being excreted in 24 h as the glucuronide conjugate of the 4′-hydroxy derivative.  相似文献   

9.
Two radiolabelled forms of racemic [14C]cypermethrin (14C at the benzylic carbon or at C-1 of the cyclopropane ring) were separately administered twice daily to lactating cows in portions of the feed. The amounts dosed were equivalent to 0.2, 5 and 10 μg of cypermethrin per g of feed. The radioactivity eliminated in the milk indicated that the ingestion and elimination of radioactivity were in balance at about day 4 after the start of dosing. Urine and faeces were equally the major routes of elimination, and only a fraction of a percent of the dose appeared in the milk. The residue in the milk was unchanged cypermethrin and was found at a concentration that was proportional to the dose. At the high cypermethrin intake of 10 μg g?1 of diet, the residue in the milk was 0.03 μg g?1. Concentrations of residues in the tissues, measured after 7, 20 or 21 days of treatment, were low and in the order: liver>kidney>renal fat>subcutaneous fat>blood>muscle>brain. The major residue in the liver and kidney of a cow that received 10 μg of cypermethrin per g of diet was N-(3-phenoxybenzoyl)glutamic acid. Other conjugates of 3-phenoxybenzoic acid and of 3-(4-hydroxyphenoxy)benzoic acid (unidentified, with the exception of the glycine conjugate) were also present. The residue in fat (about 0.1 μg g?1 from an intake of 10 μg g?1 of feed) consisted mainly of cypermethrin.  相似文献   

10.
The excretion and metabolism of cis + trans-[14C-benzyl] cypermethrin has been compared in quail, rat and mouse. Radioactivity was rapidly eliminated by quail dosed orally with [14C]cypermethrin (2 mg kg?1), as was the case in the rat and the mouse. When the birds were dosed intraperitoneally (IP) with the 14C-labelled pyrethroid, radioactivity was excreted more slowly than after oral dosing, and almost 20% of the IP dose of 14C remained in the tissues after 7 days. Both mammalian species excreted [14C]cypermethrin more rapidly than did the avian species after IP administration, and less than 6% of the dose remained in their tissues after several days. The biotransformation of the pyrethroid was more complex in the avian species (34 metabolites) than in the two mammals (some 10 metabolites in each species). In quail the predominant reactions were ester bond cleavage of cypermethrin together with either aromatic hydroxylation or amino acid conjugation of the 3-phenoxybenzyl moiety. The hydroxylated derivatives were eliminated mainly as sulphates. 3-Phenoxybenzoic acid was conjugated with a variety of amino acids including glycine, taurine, glutamic acid, serine, α-N-acetylornithine and the dipeptide glycylualine. The last two conjugations are unique to avian species. The major metabolite of cypermethrin in the rat was the sulphate conjugate of 3-(14-hydroxyphenoxy)benzoic acid, whereas in the mouse the major products were 3-phenoxybenzoic acid and its taurine conjugate. Thus, in the mammalian species where hydroxylation was maximal, amino acid conjugation was a minor metabolic route und vice versa. However, in the quail, aromatic hydroxylation and amino acid conjugation of the 3-phenoxybenzyl moiety of cypermethrin were both major reactions. The influence of the rates and sites of metabolism, and of the enzymology of amino acid conjugation, in determining this species difference are discussed. The rapid metabolism of cypermethrin to a variety of polar conjugates that are readily excreted, together with the low brain sensitivity of birds compared with mammals to its neurotoxic effects, explains the low acute toxicity of this pyrethoid to avian species.  相似文献   

11.
Isolated rat hepatocytes were incubated for 4 hr with [phenyl-U-14C]2,4,5-trimethyl-N-phenyl-3-furancarboxamide ([14C]methfuroxam). 14C-Labeled metabolites were isolated by solvent extraction, column chromatography, and high-pressure liquid chromatography, and were then characterized by analysis of infrared and mass spectra. Metabolism of [14C]methfuroxam by isolated hepatocytes included: (1) hydroxylation of the 2-, 4-, and 5-methyl groups on the furan ring; (2) hydroxylation at the para position of the benzene ring; (3) combinations of 1 and 2; (4) the addition of a sulfur-containing adjunct to the methylfuran moiety; and (5) conjugation of 1–4. Rats given a single intragastric dose of [14C]methfuroxam excreted 56% of the 14C in the urine and 42% in the feces within 54 hr. Metabolism of [14C]methfuroxam by the intact rats included: (1) hydroxylation of the methylfuran moiety; (2) hydroxylation of the benzene ring; (3) the addition of S-methyl, methyl sulfoxide, and other sulfur-containing groups to methfuroxam; (4) combinations of 1–3; and (5) conjugation of 1–4.  相似文献   

12.
A single dose (4 mg kg?1) of 14 C-labelled (R)-flamprop-methyl to rat was rapidly metabolised and 90% of the dose was eliminated in urine and faeces within 48 h. Four days after dosing, tissue residues were 0–1 μg equivalents g?1 tissue or much less, with the exception of kidney (0–22 μg g?1). There was a statistically significant sex difference in the routes of elimination; this may be attributed to differences in the biliary elimination of the major metabolite, flamprop acid, or its glucuronide conjugate. The fate of racemic flamprop-methyl was very similar to that of the (R)-isomer. The major metabolic routes were hydrolysis of the esters to the corresponding acids, hydroxylation of the benzoyl aromatic rings and conjugation. The flamprop acid derived from the (R)-flamprop-methyl was found to be partially converted to the (S)-form (R:S ratio, 87:13). This reaction is discussed in the context of other such biological racemisations recently reported.  相似文献   

13.
The metabolism of cyprodinil, a novel broad-spectrum fungicide, was investigated in rats. After single oral administration of 0.5 or 100 mg kg−1 body weight, [phenyl-U-14C]cyprodinil was rapidly eliminated, principally in the urine. The metabolite pattern in urine exhibited a significant sex-related difference with respect to the major metabolite. Males and females both produced a dihydroxy metabolite, N-4-(hydroxyphenyl)-4-cyclopropyl-5-hydroxy-6-methylpyrimidin-2-ylamine. Female rats conjugated this metabolite with sulfate exclusively at the 5-hydroxypyrimidinyl moiety, while males formed equal amounts of the monosulfate and a disulfate conjugate. The sex dimorphism in the conjugation reaction indicates the involvement of a sex-specific sulfotransferase that catalyzed the transfer of the second sulfate group.  相似文献   

14.
The metabolic fate of 14C-labeled chlorotoluron, i.e., 1-(3-chloro-4-methyl[4C]-phenyl)-3,3-dimethyl urea, was followed in rats. After a single oral dose the radioactivity was preferably excreted with the urine. Nine of the eleven urinary metabolites isolated, were identified by spectroscopic and derivatization techniques, whereas the structure of the remaining two metabolites was only partially elucidated. N-Demethylation and stepwise oxidation of the ring methyl group to hydroxymethyl and carboxyl derivatives were found as the major metabolic mechanisms. Both mechanisms proceeded simultaneously so that the isolated metabolites showed all combinations of N-demethylation and ring methyl group oxidation in their structures. One of these metabolites was an N-formyl derivative, being probably an intermediate product of demethylation. In the urine of rats fed doses of [14C]chlorotoluron higher than 50 mg/kg three additional metabolites with different degrees of N-dealkylation were found, the ring methyl group of which was transformed to a methylthio methyl group. The metabolites identified in the faeces were of the same type as those found in the urine. Based on the structures of the metabolites elucidated, a metabolic pathway of chlorotoluron in the rat is presented.  相似文献   

15.
A single oral dose of 0.14 mg kg?1 of [14C] flocoumafen to rat, which gave a transient, non-lethal, effect, was rapidly absorbed, radioactivity appearing in the blood maximally at 4 h and falling to half maximum value by 8 h. The maximum effect on prothrombin time was at 24 h and the value returned to normal by 48 h. Elimination of radioactivity was very slow, with less than 0.5% of the dose in the urine up to 7 days after dosing, and 23-26% in the faeces (more than half of which appeared in the first 24 h). Most of the administered radioactivity (74-76%) was retained 7 days after dosing. Approximately half of the dose was in the liver; it was eliminated with a halflife of 220 days. At 48 h after dosing, most of the hepatic radioactivity comprised unchanged flocoumafen. Treatments of flocoumafen-dosed rats with warfarin or with cytochrome P450-inducing doses of phenobarbitone were without effect on the hepatic residue of flocoumafen.  相似文献   

16.
The metabolism of the carbamate insecticide bendiocarb (2,2-dimethylbenzo-1, 3-dioxol-4-yl methylcarbamate) has been investigated in male and female rats and in a male human volunteer using radiolabelled material. The compound was rapidly and extensively absorbed and completely metabolised following oral administration. In man, absorption was complete, >99% of the dose being excreted in the urine within 22 h. In the rat, > 86% of the radiolabel was excreted in the urine within the first 24 h. Faecal excretion from the rat was minor (3–8% of dose) and a small amount of the compound (1–3%) was metabolised and excreted as [14C]carbon dioxide. The major metabolic pathway in both species involved cleavage of the carbamate ester group to yield the phenol,2,2-dimethylbenzo-1, 3-dioxol-4-ol (I). This metabolite, occurring as sulphate and glucuronide conjugates, accounted for more than 95% of the dose excreted by the human volunteer. In man, small amounts of conjugates of 2, 2-dimethylbenzo-1, 3-dioxol-4-yl N-(hydroxymethyl)carbamate (II) were also found in early samples. In the rat, the metabolism was more complex with the formation of small amounts of conjugates of II and several minor metabolites, thought to be ring-hydroxylated derivatives of bendiocarb and I.  相似文献   

17.
When [14C]F3-fluorodifen (2,4′-dinitro-4-trifluoromethyl diphenylether), carbonyl-[14C]CDAA (N,N-diallyl-2-chloroacetamide), and carbonyl-14C-propachlor (2-chloro-N-isopropylacetanilide) were fed to rats, 57 to 86% of the 14C was excreted via the urine within 48 hr. Although very little radioactivity was excreted in the feces of CDAA-treated rats, 15–22% of the 14C was excreted in the feces of propachlor- of fluorodifentreated rats and an average of 8% of the 14C remained in these rats 48 hr after treatment. Oxidation of the 14C label to [14C]O2 was not a major process in the metabolism of these herbicides. The only major radioactive metabolite present in the 24-h urine of fluorodifen-treated rats, 2-nitro-4-trifluoromethylphenyl mercapturic acid, accounted for 41% of the administered dose of 14C. In the metabolism of CDAA, the corresponding mercapturic acid accounted for 76% of the dose; it was the only major metabolite present in the 24-h urine. In contrast, three major metabolites were detected in the 24-h urine of propachlortreated rats, and the mercapturic acid accounted for only 20% of the dose. The mercapturic acid of each herbicide was identified by mass spectrometry.  相似文献   

18.
A goat given a single dose of 14C-labeled α-[p-(1,1,3,3-tetramethylbutyl)phenyl]-ω-hydroxyhexa(oxyethylene) ([14C]TOP-6EOH) eliminated 18% of the 14C in the urine and 77% in the feces within 96 hr after dosing. Another goat (surgically modified for total bile collection) given a single dose of [14C]TOP-6EOH eliminated 81% of the 14C in the bile, 17% in the urine, and only 6% in the feces. When 14C-bile from the animal in the second study was perfused into the small intestine of a third goat, 72% of the 14C was eliminated in the feces, 20% in the bile, and 6% in the urine within 96 hr. Eighteen different types of metabolites accounting for most of the 14C in the bile and urine were isolated, derivatized, and then characterized by mass spectral analysis. The [14C]TOP-6EOH was metabolized by: (i) oxidation of the alkyl group to give alcohols and acids, (ii) oxidation of the terminal ethylene oxide moiety to an acid, (iii) cleavage of the polyoxyethylene side chain, (iv) combinations of i–iii, and (v) conjugation of the products of i–iv.  相似文献   

19.
A single oral dose of [14C]tridemorph was partly, but rapidly absorbed by rats. Most of the radioactivity was excreted with a half-life of about 15 h. During 5 days, 42.6% was excreted in the urine, 46.7% in the faeces, 1.5% in the expired air and 3.4 % was still retained. 24 % was excreted in the 48 h bile. Sequential wholebody autoradiography indicated that much of the radioactivity was confined to the gastrointestinal tract, liver and kidneys. There was no unexpected uptake of radioactivity. Urinary metabolites were more polar than tridemorph and were also detected in the bile and faeces. The major metabolite in 24 h urine, accounting for 22.3% of the dose appeared to be a side-chain hydroxylated derivative. Cleavage of the morpholine ring was limited to about 1.5 % of the dose.  相似文献   

20.
The metabolism of the pyrethroid insecticide WL85871, labelled in the alcohol moiety, has been studied in male and female Wistar rats at a dose of ca 2 mg kg?1. The compound was rapidly broken down and the radioactivity was mainly eliminated in the urine as the sulphate conjugate of 3-(4-hydroxyphenoxy)benzoic acid (40% of the dose). Some hydroxylation occurred before ester cleavage. Approximately 20% of the ingested compound was not absorbed and was eliminated unchanged in the faeces. There was no evidence for any racemisation of the chiral centres of WL85871 either in the intestine, the faeces or in fat. The small proportion of the dose stored in adipose tissue was eliminated with biphasic kinetics (t½ values, 2–3 days and 17–26 days). The t½ values for skin were, respectively, 2 days and 40 days. As the residue in fat depleted between 3 and 40 days, an increasing proportion (from 28% to 48%) was present as a lipophilic metabolite of WL85871, or of 3-phenoxybenzoic acid, probably a mixture of 3-phenoxybenzoyl diacyl glycerols.  相似文献   

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