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1. Two [(14)C]-labelled brominated diphenyl ethers, 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) and decabromodiphenyl ether (BDE-209), were separately administered to the male Sprague-Dawley rat as a single oral dose (2.2 mg kg(-1) body weight and 3.0 mg kg(-1), respectively). 2. Very low [(14)C] urine excretion was observed for both congeners (<1% of the dose), and cumulative biliary excretion was approximately 4% for BDE-99 and 9% for BDE-209. 3. More than 6% of the pooled urine from the BDE-99-treated rat was protein-bound to an 18-kDa protein characterized by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and Western immunoblot analysis as alpha(2u)-globulin. Eighteen per cent of the radioactivity from the pooled urine from the BDE-209 treated rat was bound to albumin; no binding to alpha(2u)-globulin was detected. 4. In bile, 27-39% of the radioactivity from the BDE-99-dosed rat was bound to an unidentified 79-kDa protein, whereas essentially all (>87%) of the biliary radioactivity from BDE-209 was bound to the 79-kDa protein. Both parent BDE-99 and-209 and their metabolites were detected by thin layer chromatography in the extracted fraction of this bile protein. 5. By differential centrifugation, the subcellular localization of the (14)C derived from each congener in selected tissues was quantified. The cytosolic [(14)C] from livers of the BDE-209-treated rat was bound to a 14-kDa protein, which was characterized as a fatty acid-binding protein.

1. A disposition, metabolism and excretion study of orally administered 2,2',4,4',5-pentabromodiphenyl ether (BDE-99) was conducted in the conventional and bile duct-cannulated male rat. 2. In the conventional rat, >50% of the radiolabelled dose was retained at 72 h, and lipophilic tissues were the preferred sites for disposition, i.e. adipose tissue, adrenals, gastrointestinal tract and skin. 3. Urinary excretion of BDE-99 was very low (<1% of dose), and glucuronidation of phenolic metabolites was suggested. 4. Biliary excretion of BDE-99 was slightly greater than observed in urine, i.e. 3.6% at 72 h. 5. Over 43% of the dose in the conventional male rat and 86% in the bile duct-cannulated rat was excreted in the faeces, mainly as the unmetabolized parent compound. 6. Metabolites in bile and faeces were not conjugated. Mono- and di-hydroxylated pentabromodiphenyl ether metabolites were characterized by mass spectrometry. Two thiol metabolites were characterized in the bile. Oxidative debromination was also observed in the faecal metabolites. 7. Tissue BDE-99 was readily extractable, except for in the liver. The tissue (14)C was not associated with lipids and was mainly the unmetabolized parent compound. 8. Total thyroxine (T4) plasma levels were elevated at 3 and 6 days, and returned to control levels by day 12.

1. The possibility of using hepatocytes from food-producing animals in order to determine the metabolic routes of pesticides has been studied using a strobilurin fungicide (BAS 490 F). Hepatocytes suspensions were prepared from goat, pig, hen, and rat and the major metabolites were compared with those obtained in vivo. 2. The hepatocytes gave metabolite patterns matching qualitatively with in vivo results, but no good quantitative correlation was found. 3. A freezing and thawing method was developed using liquid nitrogen and a programmable freezer, which allows acceptable recoveries of functional cells as assessed by glutathione and cytochrome P450 contents, and phase I and II enzymatic activities (including 7-ethoxycoumarin-O-deethylase, ethoxyresorufin-O-deethylase, glutathione-S-transferase, and UDP-glucuronosyl transferase), with 60-70% viability. 4. The cells were damaged through freezing as indicated by the efflux of glutathione (40-60% of the intracellular content), but remained able to metabolize BAS 490 F, partially like fresh cells. A good qualitative but no quantitative matching of the metabolite patterns before and after cryopreservation was found, indicating that the metabolic activities are affected to variable extents during the freezing process. 5. The use of fresh and cryopreserved cells as models for metabolism and species comparison, and as a versatile tool to synthesize metabolites, is discussed.

1. The effects of oxygen concentration were studied on the metabolic pathways of anisole homologues (anisole, phenetole and isopropoxybenzene) catalysed by liver microsomes from phenobarbital-treated rats. 2. With increase of oxygen concentration, the rate of anisole o-hydroxylation reached a plateau at about 35 microM O2, while the rates of O-demethylation and aromatic p-hydroxylation were still increasing at 223 microM O2 (air). 3. The rates of all three metabolic reactions of phenetole reached plateau levels at about 80 microM O2. 4. The rates of all three metabolic reactions of iso-propoxybenzene were still increasing as 223 microM O2 (air). 5. The ratio of aromatic p-hydroxylation or O-dealkylation to aromatic o-hydroxylation decreased in anisole metabolism, and showed no uniform change in phenetole and isopropoxybenzene metabolism with decreasing oxygen concentration. 6. The ratio of aromatic p-hydroxylation to O-dealkylation was essentially constant over the range of oxygen concentration studied in anisole and phenetole metabolism, while in iso-propoxybenzene metabolism the ratio was different between higher and lower oxygen concentrations than 60 microM. 7. This series of compounds with increasing chain length did not show homologous changes in rates of product formation or O2 dependent of product formation.

1. The metabolism of fomocaine following its oral administration to male and female Wistar rats and male beagle dogs has been qualitatively investigated. 2. The drug is metabolized in both species by aromatic hydroxylation, N-oxidation, splitting of the ether link and, in the dog, by removal of the morpholine group. 3. The rat and dog excrete some unchanged fomocaine in the urine together with p-hydroxyfomocaine (free and conjugated), fomocaine-N-oxide, p-hydroxyfomocaine-N-oxide and p-(gamma-morpholinopropyl)benzoic acid. In addition, the dog excretes morpholine in the urine.

1. The major metabolic transformation of orally ingested 14C-DGEBPA is by hydrolytic ring-opening of the two epoxide rings to form diols. This metabolite (the bis-diol of DGEBPA) is excreted in both free and conjugated forms and is further metabolized to various carboxylic acids, including two containing a methylsulphonyl moiety. 2. The product of oxidative dealkylation either of DGEBPA (with concomitant formation of glycidaldehyde) or of the bis-diol of DGEBPA (with concomitant formation of glyceraldehyde) is excreted in both free and conjugated forms in amounts representing 5% of the dose. 3. The high activity of epoxide hydratase towards DGEBPA suggests that glyceraldehyde and not glycidaldehyde is formed in vivo. 4. Hepatic epoxide hydratase activity towards DGEBPA measured in vitro decreased in the order rabbit greater than mouse greater than rat. 5. Two discrete epoxide hydratases are present in large amounts in the mouse. One is membrane-bound in the liver microsomal fraction and the other is a "soluble' enzyme located in the liver cytosol. This cytosolic enzyme was present in only very small amounts in the rat.

1. 3-Phenoxy[14C]benzoic acid administered orally to rats (0.76 to > 100 mg/kg) is extensively metabolized and rapidly eliminated mostly via the urine. 2. The major metabolic pathway involves 4'-hydroxylation followed by conjugation of the resulting phenol with sulphate. Only minor amounts of amino acid and glucuronic acid conjugation were observed. 3. 3-Phenoxy[14C]benzoyl glucoside, derived from the metabolism of the acid by corn leaves, was also rapidly absorbed by rats and eliminated as a mixture of metabolites very similar to that derived from 3-phenoxybenzoic acid. It was concluded that the glucoside conjugate was rapidly hydrolysed to the free acid in vivo.

1. 14C-DGEBPA dermally applied to mice was only slowly eliminated in the feces (20% dose) and urine (3%), as a mixture of metabolites, over three days. Most of the applied radioactivity (66% dose) was extracted from the application area and its covering foil. 2. When 14C-DGEBPA was given orally to mice it was rapidly excreted; 80% of the administered 14C was eliminated in the feces and 11% in the urine 0-3 days after a single oral dose. 3. The urinary faecal metabolite profiles derived from dermal application and oral dosing were essentially similar.

1. 3-Phenoxy[14C]benzoyl-CoA has been chemically synthesized, purified and characterized by field-desorption mass spectrometry. Biological activity of the purified thioester was greater than 92%. 2. The two enzymic steps involved in the conjugation of 3-phenoxybenzoic acid (3PBA) with glycine have been investigated in hepatic and renal tissues from various mammalian species. 3. A 10- to 300-fold excess of acyl-CoA: glycine N-acyltransferase activity as compared with acyl-CoA synthetase activity was found in most tissue preparations, while the rate of the activating step matched that of the overall process. This suggests that formation of the acyl-CoA thioester (3PBA-CoA) is the rate-limiting step in the conjugation of 3PBA with glycine. 4. In most of the species tested, renal activities were higher than those of corresponding liver preparations. 5. The gerbil and ferret, which excrete 3-phenoxybenzoylglycine as the principal urinary metabolite of 3PBA, gave the highest 3PBA-CoA synthetase and glycine N-acyltransferase activities in vitro. By contrast, the hamster, which excretes only small amounts of the glycine conjugate of 3PBA, had the lowest enzymic activities in vitro. 6. In the mouse and rat there were differences between the patterns of metabolism found in vivo and in vitro, and possible reasons for this are discussed.

1. In the rat chlorodiphenyl ethers are metabolized via two routes. The predominant reaction is aromatic hydroxylation; scission of the ether bond is a minor metabolic process. 2. In all cases, primary hydroxylation takes place ortho and meta to the ether bond. Ortho-hydroxylation leads to the formation of 'predioxins' in cases where the parent compounds contain a chlorine atom in one of the ortho positions in the second ring. 3. 5-Chloro-2-(2,4--dichlorophenoxy)phenol (Irgasan DP 300), a compound that meets the structural requirements of a predioxin, did not yield chlorodibenzo-p-dioxins or hydroxylated derivatives thereof. 4. Irgasan DP 300 is excreted unchanged in faeces and urine (partly conjugated) but is also hydroxylated to five different monohydroxy metabolites which were found in urine; three of these were also present in faeces. As a result of scission of the ether bond 2,4-dichlorophenol occurred in urine and faeces, and 4-chlorocatechol in urine. 5. Neither in the case of Irgasan DP 300, nor in that of chlorodiphenyl ethers with an ortho chlorine atom, could metabolic cyclization to chlorodibenzofurans or their hydroxylated derivatives be detected.

Diphenyl ether (DPE) was administered intraperitoneally to rainbow trout (Salmo gairdneri) and guinea-pigs (Duncan Hartley). DPE metabolites in the urine and bile of trout and the urine of guinea-pigs were isolated and analysed by g.l.c.-mass spectrometry. No unchanged DPE was found in the biological fluids of guinea-pigs and trout. Only conjugated metabolites of DPE were present in the bile and urine of the trout: 4-hydroxy- and possible 3-hydroxy-DPE conjugates were found in the bile whereas 4-hydroxy- and 4,4-dihydroxy-DPE conjugates were detected in the urine. Both free and conjugated metabolites of DPE were isolated from the urine of guinea-pigs. These metabolites were 2-hydroxy-, 4-hydroxy, 4,4'-dihydroxy-, 4-methoxy-monohydroxy- and methoxy-dihydroxy-derivatives of DPE.

1. The metabolism of butyl p-nitrophenyl ether in vitro has been investigated with rabbit liver preparations. 2. Evidence for three metabolic pathways is presented. These involve initial microsomal hydroxylation at alpha, omega--1 or the omega positions of the butyl chain. 3. (omega--1)-Hydroxybutyl p-nitrophenyl ether was oxidized chiefly by the soluble fraction to the corresponding (omega--1)-oxo derivative which spontaneously decomposed to give p-nitrophenol. 4. omega-Hydroxybutyl p-nitrophenyl ether identified as a metabolite was further oxidized by the soluble fraction to p-nitrophenoxybutyric acid.

1. A substantial proportion of the radioactivity of an oral dose (1-20 mg/kg) of 3-phenoxy [14C] benzoic acid and the pyrethroid insecticide trans- and cis-[aryl-14C] cypermethrin (an alpha-cyano-3-phenoxybenzyl ester) is eliminated rapidly in urine of mice. 2. The major urinary metabolite of these compounds in two strains of mice is N-(3-phenoxybenzoyl)taurine. 3. Neither 3-phenoxybenzoic acid nor cypermethrin gives a taurine conjugate in rats. 4. Benzoic acid gives no taurine conjugate in mice.

1. Urinary and faecal excretion of radioactivity in 120 h after oral administration of [U-14-C]phenyl o-(2-N-morpholinoethoxy)phenyl ether hydrochloride (200 mg/kg) were 92 and 3% dose in the rabbit, and 60 and 35% in the rat. 2. Urinary metabolites were produced by aromatic hydroxylation and aryl alkyl ether bond cleavage. Some evidence for formation of dioxomorpholino, oxohydroxymorpholino, and ethanolamino derivatives of the drug was obtained. 3. The aromatic hydroxylation product, p-hydroxyphenyl o-(2-N-morpholinoethoxy)phenyl ether hydrochloride had vasopressor activity comparable with the parent compound, but with shorter duration of action.

After i.p. administration of [14C]diphenyl ether (5 mg/kg) to rats, radioactivity was detected rapidly in all organs and tissues. After intragastric administration of [14C]diphenyl ether (10 mg/kg) to rats, unchanged diphenyl ether in the blood was at max. concn. within 15 h and decreased linearly with time, with a biological half-life of about 1.5 h. More than 90% of the intragastrically administered dose was excreted in urine and faeces within three days; greater than 80% dose was in the urine. From g.l.c. and mass-spectral data, it was shown that rats metabolized diphenyl ether to its 2-hydroxy, 4-hydroxy, 4,4'-dihydroxy, 4-methoxy-monohydroxy and 4-methoxy-dihydroxy derivatives.