The metabolism of benodanil in the rat

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.     

The metabolism of the pyrethroid insecticide (±)-α-cyano-3-phenoxybenzyl 2,2,3,3-tetramethyl-cyclopropanecarboxylate,WL 41706, in the rat

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.     

The fate of the rodenticide flocoumafen in the rat: Retention and elimination of a single oral dose

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.     

Metabolism in rats of 3-phenoxybenzyl alcohol and 3-phenoxybenzoic acid glucoside conjugates formed in plants

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.     

Metabolism and fate of triazophos in rats

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.     

The metabolism of the herbicide flamprop-methyl in rats and some comparative data for dogs,mice and rabbits

[¹⁴C]Flamprop-methyl administered orally to rats (3-4 mg kg^?1 body weight) was excreted mostly via the faeces (78.7 and 61.6% in males and females, respectively). Elimination was rapid and 90% of the dose of ¹⁴C was excreted in faeces and urine 0-48 h after dosing. The distribution of ¹⁴C between faeces and urine was different in males and females. No expired [¹⁴C]carbon dioxide was detected and less than 2% of the dose remained in the animals 4 days after dosing. The predominant metabolic pathway was hydrolysis of the ester bond to afford the carboxylic acid which was excreted unchanged and as its glucuronide conjugate. Aromatic hydroxylation occurred at the para- and meta-positions of the N-benzoyl ring. N-(3)-Chloro- 4-fluorophenyl-N-(3,4-dihydroxybenzoyl)-DL -alaninate was also formed. This hydroxylated form of flamprop-methyl was partially O-methylated at the 3-hydroxy group. Flamprop-methyl was also metabolised and eliminated rapidly by dogs, mice and rabbits. The last of these three species afforded very little aromatic hydroxylation and also differed from the others in that the metabolites were eliminated mostly in the urine. Aromatic hydroxylation lay in the order: male rat = female rat > dog= mouse>rabbit (female).     

Mercapturic acid formation in the metabolism of propachlor,CDAA, and fluorodifen in the rat

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.     

The metabolism of [14C] cymoxanil in the rat

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.     

The metabolism of cis-2,5-dimethylpyrrolidine-1-carboxanilide in rodents

The metabolism of cis-2,5-dimethylpyrrolidine-1-carboxanilide was studied in rats, rabbits, guinea-pigs and mice. The major metabolite in all species was cis-4′-hydroxy-2,5-dimethylpyrrolidine-1-carboxanilide, both free and as glucuronide and sulphate conjugates. About 95% of the compound was absorbed from the gut; over a 3-day period, about 50% of the administered dose was excreted in urine and about 27% in faeces.     

The metabolism of the carbamate insecticide bendiocarb in the rat and in man

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.     

The metabolism of chlorotoluron in the rat

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.     

The bioaccumulation and biotransformation of cis,trans-cypermethrin in the rat

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.     

The metabolism of tefluthrin in the goat

A goat was dosed orally with [¹⁴C]tefluthrin, twice daily for 4 days, at a rate equivalent to 10.9 mg kg^?1 in its diet. Within 16 h of the final dose, 70.1% of the dose had been excreted (urine 41.4%, faeces 28.7%). Extensive metabolism occurred in the goat by ester cleavage and oxidation at a variety of positions on the molecule. Low radioactive residues were detected in the milk (0.076 mg kg^?1), fat (0.076 mg kg^?1) and muscle (0.016 mg kg^?1), with tefluthrin as the largest individual component of the residue (milk 66.5%, fat 76.7%, muscle 34.2%). Higher residues were present in the kidney (0.3 mg kg^?1) and liver (1.0 mg kg^?1) and only a small percentage of this residue was due to tefluthrin (kidney 3.4%, liver 6.1%). The remainder of the residue in the kidney and liver was a complex mixture of metabolites. Most of the kidney metabolites were identified, but a high proportion of the liver residue was due to six unidentified polar compounds.     

Degradation of triphenyltin chloride on sugar beet plants and in rats

The degradation of triphenyltin chloride on the leaves of sugar beet proceeds via di- and mono-phenyltin compounds to inorganic tin( IV ). This degradation scheme has also been observed in rats, as the same metabolites were found in urine and faeces of these animals. After a single application of triphenyltin chloride, more than 90% of the tin given is excreted within one week (approx. 88% with the faeces and approx. 3% with the urine). The experiments were performed with radioactive (C₆H₅)₃¹¹³SnCl.     

Fate of captan and folpet in rats and their effects on isolated liver nuclei

Excretion and distribution of single and multiple intraperitoneal doses of [³⁵S]captan and [¹⁴C]folpet were similar in normal and 70% hepatectomized male rats. After receiving the single dose of captan, the rats eliminate approximately 76% of the radioactivity in the urine after 72 hr. The elimination in the feces for the same time period was 13%. Normal rats administered single or multiple doses of [¹⁴C]folpet excreted nearly 100% of the total dose in the urine within the first 24 hr. Nuclei isolated from the liver of normal and 70% hepatectomized rats receiving multiple doses of [³⁵S]captan contained 0.008–0.009 μg ³⁵S/g of tissue. Appreciable amounts of the radioactivity from [³⁵S]captan were bound by isolated nuclei from the livers of normal and partially hepatectomized rats. After a 1-hr treatment with [³⁶S]captan, the nuclei were fractionated into nuclear sap protein, deoxyribonucleoprotein (including histones), acidic ribonucleoprotein, and “residual” protein fractions. These proteins in normal nuclei bound 10, 14, 39, and 16% of the total label, respectively, with essentially the same results obtained with nuclei from regenerating rat liver. When compared by polyacrylamide gel electrophoresis, acidic nuclear proteins from treated and nontreated normal nuclei were characterized by band diffusion and the presence or absence of Amido Schwartz-staining bands. None of the abovementioned effects on histones from treated nuclei were observed. Captan treatment of isolated nuclei also altered the extraction characteristics of the nuclear protein fractions, presumably because of extensive aggregation of thiol-containing nuclear proteins.     

The metabolic fate in rats of the pyrethroid insecticide WL85871, a mixture of two isomers of cypermethrin

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.     

Conversion of the aldrin/dieldrin metabolite dihydrochlordene dicarboxylic acid-14C in rats

Upon intravenous application of dihydrochlordene dicarboxylic acid-¹⁴C to rats, the radioactivity is quickly excreted, and 44% of the excreted radioactivity consists of metabolites. Nine metabolites have been isolated from feces and urine extracts. Three metabolites could be identified by means of authentic samples by thin layer chromatography, gas chromatography, and mass spectrometry: two isomers of dechlorodihydrochlordene-dicarboxylic acid (metabolites I and II, total 22.5%) and dihydrochlordene-dicarboxylic acid-dimethyl-ester (metabolite III, 11.3%).     

Animal metabolism of propham (isopropyl carbanilate): The fate of residues in alfalfa when consumed by the rat and sheep

Alfalfa was root-treated with [¹⁴C]propham (isopropyl carbanilate[¹⁴C-phenyl(U)]) for 7 days and then harvested and freeze-dried. Rats and sheep were orally given either ¹⁴C-labeled alfalfa roots ([¹⁴C]root) or ¹⁴C-labeled alfalfa shoots ([¹⁴C]shoot). When the [¹⁴C]root was given, 6.5–11.0% of the ¹⁴C was excreted in the urine and 84.6–89.4% was excreted in the feces within 96 h after treatment. Less than 3% of the ¹⁴C remained in the carcass (total body—gastrointestinal tract and contents) 96 h after treatment. When [¹⁴C]shoot was given, 53.2–55.2% of the ¹⁴C was excreted in the urine, 32.1–43.4% was excreted in the feces, and the carcass contained 0.2–1.1% of the ¹⁴C 96 h after treatment. When the insoluble fraction (not extracted by a mixture of CHCl₃, CH₃OH, and H₂O) of both alfalfa roots and shoots was fed to rats, more than 86% of the ¹⁴C was excreted in the feces and less than 3% remained in the carcass 96 h after treatment. The major radiolabeled metabolites in the urine of the sheep fed ¹⁴C shoot were purified by chromatography and identified as the sulfate ester and the glucuronic acid conjugates of isopropyl 4-hydroxycarbanilate. Metabolites in the urine of the sheep treated with [¹⁴C]root were tentatively identified as conjugated forms of isopropyl 4-hydroxycarbanilate, isopropyl 2-hydroxycarbanilate, and 4-hydroxyaniline. The combined urine of rats dosed with [¹⁴C]shoot and [¹⁴C]root contained metabolites tentatively identified as conjugated forms of isopropyl 4-hydroxycarbanilate, isopropyl 2-hydroxycarbanilate, and 4-hydroxyaniline.     

The metabolism of the nonionic surfactant 14C-labeled α[p-1,1,3,3-tetramethylbutyl)phenyl]-ω-hydroxyhexa(oxyethylene) in the goat

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.     

In vivo pharmacokinetics of pyribenzoxim in rats

Pyribenzoxim, benzophenone O‐[2,6‐bis(4,6‐dimethoxypyrimidin‐2‐yloxy)benzoyl]oxime, is a new post‐emergence herbicide providing broad‐spectrum weed control in rice fields. [¹⁴C]Pyribenzoxim was used to study the pharmacokinetics of the compound after oral administration of a dose of 1000 mg kg^?1 to male Sprague–Dawley rats. The material balance ranged from 97.3 to 99.7% of the administered dose and urinary and fecal recovery accounted for 97.1%, with the majority of radioactivity recovered in feces (88.6%) by 168 h after treatment. Elimination as volatile products or as carbon dioxide was negligible. The following values were obtained for the compound in the blood: AUC_0–168h, 28400 µg equiv h g^?1; T_max, 12 h; C_max, 372 µg equiv g^?1; half‐life, 53 h. Radioactivity in tissue decreased from 96.1% of applied radiocarbon at 6 h to 0.4% at 168 h and the highest concentration of radioactivity among the tissues was observed in liver while the lowest residues were found in brain. The elimination half‐lives of radioactivity from tissues was in the range of 7 to 77 h and T_max values of 12, 24 and 12 h were observed for blood, liver and kidney, respectively. Except for that in the digestive tract, the tissue‐to‐blood ratio (TBR) was highest in the liver. © 2001 Society of Chemical Industry