Abstract: 1. The anti-inflammatory agent diclofenac sodium (o-[(2,6-dichlorophenyl)amino]phenylacetic acid sodium salt) is extensively metabolized by rat, dog, baboon and man. The main metabolites were isolated from the urine of all species and from the bile of rat and dog and identified by spectroscopy. 2. Metabolism involves direct conjugation of the unchanged drug, or oxidation of the aromatic rings usually followed by conjugation. Sites of oxidation are either position 3' or 4' of the dichlorophenyl ring or, alternatively, position 5 of the phenyl ring attached to the acetic acid moiety. 3. In the urine of rat, baboon and man conjugates of the hydroxylated metabolites predominate, but the major metabolite in dog urine is the taurine conjugate of unchanged diclofenac. 4. In the bile of rat and dog, the main metabolite is the ester glucuroniade of unchanged diclofenac.

Abstract: 1. Quantitative determinations of unchanged diclofenac and two of its major phenolic metabolites were made by reverse isotope dilution analysis on urine of rat, dog, rhesus monkey, baboon and man and on bile of rat, dog and man. Isotope dilution analysis was performed before and after various methods of enzymic and chemical hydrolysis. 2. The same samples were also analysed by two-dimensional t.l.c. and subsequent autoradiography, to estimate the remaining phenolic metabolites. 3. In contrast to rat, rhesus monkey, baboon and man, which excrete mainly hydroxylated metabolites, the dog does not oxidize diclofenac. Dog urine contained a relatively stable taurine conjugate of diclofenac, and in the bile an ester glucuronide was excreted, which decomposed even in weakly alkaline soln. 4. The unstable ester glucuronide found in dog bile was also demonstrable in rat bile. It presumably hydrolyses in the duodenum, releasing diclofenac which undergoes enterohepatic circulation.

Abstract: 1. The amounts of antipyrine and its metabolites excreted in 24 h urine after i.v. injection of 10 mg antipyrine into male Wistar rats were quantified after enzymic hydrolysis with beta-glucuronidase/aryl sulphatase. In 24 h 2.7% of the administered dose was excreted as unchanged antipyrine, 13.3% as 4-hydroxyantipyrine, 7.4% as norantipyrine, 28.9% as 3-hydroxymethylantipyrine and 1.1% as 3-carboxyantipyrine. 2. Treatment with phenobarbital decreased the antipyrine half-life from 65 to 30 min, but did not significantly change the urinary metabolite profile. Only the amount of 3-carboxyantipyrine was significantly different and increased from 1.1 to 2.6% dose. 3. 3-Methylcholanthrene treatment resulted in a decrease of antipyrine half-life from 72 to 37 min. After treatment 4-hydroxyantipyrine was increased from 13.4% to 25.6% dose, whereas 3-hydroxymethylantipyrine was decreased from 26.8% to 8.5% and 3-carboxyantipyrine from 1.3% to 0.2% of the dose respectively; norantipyrine was unchanged. 4. It is concluded that different types of hepatic cytochrome P-450 may be involved in the formation of 4-hydroxyantipyrine on one hand and the formation of 6-hydroxymethylantipyrine on the other. Another possibility is that in methylcholanthrene-treated animals another haemoprotein is formed that results in the formation of more 4-hydroxyantipyrine and less 3-hydroxymethylantipyrine. In any case, the urinary metabolite profile of antipyrine can be used to study changes in the activity of different cytochromes in drug metabolism studies.

Abstract: 1. The qualitative and quantitative aspects of the urinary elimination of orally administered 4-methoxy[14C]amphetamine have been examined in the rat and guinea-pig and in three volunteer human subjects, to determine interspecies and interindividual variations in disposition of the drug.2. Both rat and guinea-pig excreted 70-80% of the administered dose (6 mg/kg) in the urine within 24 h, mainly as metabolites.3. In the guinea-pig, the drug was metabolized by O-demethylation to give 4-hydroxyamphetamine, which was excreted free (4% dose) and conjugated (73%). No other metabolite was detected.4. The rat metabolizes the drug both by O-dealkylation and by side-chain oxidation, the products being 4-hydroxyamphetamine (5% of dose free and 60% conjugated) and 1-(4'-methoxyphenyl)propan-2-one oxime (5% dose, free and conjugated).5. In man the drug (dose 5 mg) is metabolized by O-demethylation and by side-chain oxidation. Marked intersubject variations were observed both in the array and quantitative aspects of m...

Abstract: 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 tha...

Abstract: 1. Debrisoquine hydroxylation exhibited profound variation in 72 Egyptian volunteers. 2. The frequency distribution histogram of the metabolic ratio (ratio unchanged drug: 4-hydroxy metabolite in 0-8 h urine) was polymodal. 3. From family data it was possible to define more clearly than before the heterozygous characteristics. 4. Egyptians appear in general to be more extensive oxidizers of debrisoquine than do English subjects. 5. Ramadan fasting was found to lower the absorption of debrisoquine.

Abstract: 1. The metabolism of 1-bromopropane in the rat has been re-investigated. The previously known metabolites have been isolated and confirmed as the three mercapturic acids N-acetyl-S-propyl cysteine, N-acetyl-S-propyl cysteine-S-oxide and N-acetyl-S-(2-hydroxypropyl)cysteine.2. Three further metabolites have been isolated from the urine of rats treated with 1-bromopropane. These have been identified as 3-bromopropionic acid and the mercapturic acids N-acetyl-S-(3-hydroxypropyl)cysteine and N-acetyl-S-(2-carboxyethyl)cysteine.3. The metabolites of 3-bromopropanol and 3-chloropropanol in the rat have been shown to be the mercapturic acids N-acetyl-S-(3-hydroxypropyl)cysteine and N-acetyl-S-(2-carboxyethyl)cysteine and the corresponding 2-carboxyethyl halide.4. Studies with 1-bromopropane and the 3-halopropanols in vitro indicate that oxidation of C3 and C2 of 1-bromopropane occurs before conjugation of the alkyl group with glutathione. The implications of these studies are discussed in relation to the mechani...

Abstract: 1. Isoquinoline, cinnoline, quinoxaline, quinazoline and phthalazine were incubated with preparations of rabbit liver aldehyde oxidase. 2. The oxidation products, 1-hydroxyisoquinoline, 4-hydroxycinnoline, 2-hydroxy- and 2,3-dihydroxy-quinoxaline, 4-hydroxy- and 2,4-dihydroxy-quinazoline, and 1-hydroxyphthalazine were identified by comparison of their spectral and chromatographic characteristics with those of authentic compounds. 3. Michaelis-Menten constants are reported for the action of the parent heterocycles with aldehyde oxidase. The compounds reported in this study are among the most efficient substrates yet described for rabbit liver aldehyde oxidase. 4. The compounds in 1 above were incubated with bovine milk xanthine oxidase: only quinazoline and phthalazine yielded significant amounts of metabolites. Km values were calculated for these compounds. 5. Incubation of the heterocycles with rat liver preparations gave qualitatively the same results as those obtained using rabbit liver, but smaller amounts of the oxidation products were detected from rat liver incubations.

Abstract: 1. Ornidazole, labelled with 14C in the imidazole ring, administered orally to rats, dogs and men was largely excreted in the urine, predominantly as metabolites, with less than 4% of the drug being excreted unchanged. Free and conjugated metabolites were found in the ratio of approx. 1 : 2. 2. The pattern of free ornidazole and metabolites was different in the three species: while ornidazole predominated in man, ornidazole and metabolite M1 in the dog, the most extensive metabolic pattern was found in the rat. 3. The following metabolites were identified: M1, 1-chlorlo-3-(2-hydroxymethyl-5-nitro-1-imidazolyl)-2-propanol; M2, 2-methyl-5-nitroimidazole; M3, N-(3-chloro-2-hydroxypropyl)acetamide: M4, 3-(-2-methyl-5-nitro-1-imidazolyl)-1, 2-propanediol; M5, acetamide. 4. The formation of metabolite M3 and M5 indicated cleavage of the imidazole ring between N-1/C-5 and C-2/C-3. Other ring scissions were not observed. Metabolites carrying a free amino group were not detected. On the basis of the structures identified, a scheme is suggested for the metabolism of ornidazole.

Abstract: 1. The deactivation of aflatoxin B1 by glutathione (GSH) has been investigated in rat. Binding of metabolites of aflatoxin B1 to [3H]glutathione in vitro with rat liver microsomes is insignificant. Incubation with rat liver 10 000 g supernatant results in increased binding. Under identical conditions, benzo(a)pyrene metabolites are bound to [3H]glutathione much more than is aflatoxin B1. 2. Pre-treatment of rats with aflatoxin 1 (2 mg/kg) caused depletion in GSH of rat liver with a minimum at 6 h but returning to above normal at 24 h. GSH S-transferase activity was marginally increased at 6 h also and returned to normal at 24 h. 3. Kidney GSH was not significantly decreased, but kidney GSH S-transferase activity showed a sudden increase in 6 h, returning to almost normal at 24 h. 4. Pre-treatment with benzo(a)pyrene (2 mg/kg) caused greater depletion of hepatic GSH than occurred with aflatoxin B1 but did not show any effect on kidney GSH. 5. Hepatic and kidney GSH S-transferase in benzo(a)pyrene-treated rats showed greatest activity at 2 h followed by a gradual fall through 24 h. 6. GSH was therefore a less efficient nucleophile for aflatoxin B1 metabolites than for benzo(a)pyrene metabolites.

Abstract: 1. The metabolism of several dihalopropanols has been studied in the rat. Irrespective of their structure, each compound produced the same two mercapturic acids, excreted as urinary metabolites.2. The mercapturic acid metabolites of the dihalopropanols were identified as N-acetyl-S-(2,3-dihydroxypropyl)cysteine and N, N-bis-acetyl-S, S'-(1,3-bis-cysteinyl)propan-2-ol. Depending on the halogen present, each dihalopropanol produced β-chlorolactate or β-bromolactate as oxidative metabolites.3. From the metabolic pathway of these compounds, it is inferred that an epoxide is an intermediate in their metabolism.4. The metabolism of 2-chloropropane-1, 3-diol has been investigated in the rat and the isolation of one mercapturic acid, N-acetyl-S-(2,3-dihydroxypropyl)cysteine, confirms that an epoxide intermediate is involved.

Abstract: 1. (Z)-1,3-Dichloro[2-14C]propene([14C](Z)-DCP) when dosed orally to rats gave 82-84% of the radioactivity in the urine 24 h after treatment. Most of this 14C (92%) was present as N-acetyl-S-((Z)-3-chloroprop-2-enyl)cysteine ((Z)-DCP mercapturic acid).2. When (Z)-DCP was incubated with glutathione and rat liver cytosol (containing glutathione S-alkyl transferase), very rapid loss of (Z)-DCP was observed. The product of this reaction was S-[(Z)-3-chloroprop-2-enyl)]glutathione.

Abstract: 1. The N-oxidation of pyridine, 3-methylpyridine and 3-chloropyridine was inhibited by SKF525A and DPEA. The C-oxidation of 3-methylpyridine was also inhibited by these compounds. 2. The N-oxidation of these pyridines was also inhibited by various other nitrogenous substrates including n-octylamine. 3. Incubation in an atmosphere of carbon monoxide resulted in inhibition of both C- and N-oxidation of 3-methylpyridine. 4. Any treatment of microsomes which resulted in a reduction of cytochrome P-450 also produced a concomitant fall in N-oxidation of the pyridines. 5. Pretreatment of animals with phenobarbitone resulted in an increase in the N-oxidation of the pyridines. Pretreatment with 3-methylcholanthrene had no appreciable effect on the N-oxidation of the pyridines in vitro.

Abstract: 1. The metabolism in rats of several kava pyrones from Piper methysticum Forst. was studied. The compounds were the 5,6-dihydro-alpha-pyrones, dihydrokawain, kawain and methysticin, and the alpha-pyrones, 7,8-dihyroyangonin and yangonin. 2. Approx. half the dose (400 mg/kg, p.o.) of dihydrokawain was found in the urine in 48 h. About two-thirds of this was hydroxylated metabolites (three mono- and three di-hydroxylated derivatives), of which p-hydroxydihydrokawain was the most abundant. The remaining third consisted of metabolites formed by scission of the 5,6-dihydro-alpha-pyrone ring and included hippuric acid (9--13% dose). 3. Lower amounts of urinary metabolites were excreted when kawain was given, but both hydroxylated and ring-opened products were formed. 4. Methysticin gave rise to only small amounts of two urinary metabolites formed by demethylenation of the methylenedioxyphenyl moiety. 5. Urinary metabolites of the alpha-pyrones, 7,8-dihydroxyangonin and yangonin, were formed via omicron-demethylation. No ring-opened products were detected. 6. These lipophilic kava pyrones have extremely low solubility in water, which would be expected to reduce their absorption rates and appears to be responsible for the variable and low extent of metabolism observed.

Abstract: 1. Following an oral dose of [14C]phenol (12·5 or 25 mg/kg) to sheep, pig and rat, urinary elimination of radioactivity was rapid, 80-90% dose being excreted in the first 8h.2. In anaesthetized, ureter-cannulated rats, 70-80% of an intraduodenal dose was eliminated in 2 h; 2% dose was excreted as phenol conjugates in the urine within 10 min.3. The major urinary metabolites from phenol (25 mg/kg) were phenylglucuronide and phenylsulphate. In the sheep, pig and rat, the glucuronide accounted for 49%, 83% and 42% respectively, of the total urinary metabolites and sulphate accounted for 32%, 1% and 55%. Conjugates of quinol were minor urinary metabolites (<7%) in all three species.4. In sheep some 12% of the urinary metabolites was conjugated with phosphate; this metabolite was not found in rat or pig.

Abstract: 1. The major biliary metabolites of flavanones in the rat have been identified by chromatographic and spectral methods.2. Evidence is presented that flavanones and flavanone glycosides, following oral or parenteral administration, undergo glucuronylation and are selectively excreted via the bile.3. Flavanone glycosides but not unconjugated aglycones may be excreted to a significant extent in bile.4. The percentage of parenterally administered flavanones excreted in bile varies inversely with the amount administered.

Abstract: 1. The anthelmintics bithionol, phenothiazine, albendazole and fenbendazole were oxidized to sulphoxides by enzymes in the cytosol of the proglottids of the cestode Moniezia expansa and the cytosol of the intestinal epithelial cells of the nematode Ascaris suum. Enzymes in these tissues were also able to reduce these sulphoxides to the thioethers in the absence of oxygen. 2. Sulphoxidation and sulphoxide reduction also occurred in mouse liver enzyme preparations. About 20% of the sulphoxidation activity was not associated with microsomes and was not inhibited by CO; about 50% of the reductase activity was found in the microsomes. 3. The pH optima for sulphoxidases from both helminths were in the range 7.0--7.2, and both required NADH or NADPH for activity. Low molecular weight thiols and flavins did not affect sulphoxidation. Enzyme activity was inhibited by 0.1 mM Cu2+, Hg2+, Cd2+ or Zn2+ and by p-chloromercuribenzoate or N-ethylmaleimide. 4. Both helminth sulphoxide reductases displayed pH optima in the range 1.2--7.4, and required NADH or NADPH for activity. Oxygen inhibited the reductases.

Abstract: 1. The metabolism of noscapine was studied in rabbits, rats and human. 2. Apart from the O-demethylated metabolites already reported, three metabolites were isolated and identified as meconine, cotarnine and hydrocotamine, respectively. 3. Mass fragmentography (chemical ionization) was used to determine these products simultaneously. 4. Meconine was the major metabolite in all three species, accounting for about 3, 8 and 2% of the dose in the first 24 h urines of rats, rabbits and humans, respectively, although one woman excreted to a very high extent (22%). In rats, cotarnine bases were excreted at almost same level as that of meconine, but at lesser extent in other two species. Hydrocotamine and unchanged noscapine were excreted to less than 1% dose.

Abstract: (HCH) is converted, on incubation with the IOOOOOg supernatant fraction (cytosol) of rat liver homogenates, to four positional isomers of S-(dichloropheny1)glutathione (DCPG). 2. Radiochemical evidence shows that primary conjugates formed are subject to rapid aromatization. 3. The GSH-conjugates produced from y-HCH (Iindane), 6-HCH, and three stereoisomers of 1,3,4,5,6-pentachlorocyclohex-1 -ene (PCCH) have been characterized by g.1.c. of their aromatic moieties. All compounds were exclusively converted to at least two positional isomers of DCPG. An isomer of HCH and its trans-dehydrochlorination product yielded DCPG of almost identical composition. 4. 8-HCH was not entirely unreactive, but the identity of the product remained uncertain. 5. DCPG-formation from HCH-d, exhibited a significant deuterium isotope effect (5.8 at 310 K for the a-configuration), while none was found for the conversion of PCCH-d5'(1.2 at 298 K for the 3,4,6/5-isomer). 6. In the absence of GSH, liver cytosol protein mediated a trans-dehydrochlorination of lindane and of a-HCH to PCCH with a catalytic factor of 15 and 25, respectively. Addition of GSH raised HCH conversion by afactor of 3 to 4 and resulted in the formation of DCPG. 7. GSH-conjugation of PCCH is shown to be enzymic. 8. It is concluded that the rate of formation of DCPG from HCH in rat liver cytosol depends on gradual monodehydrochlorination, and that the enzymic transfer of GSH onto PCCH is not preceded by a second dehydrochlorination. The transfer and elimination reactions involved in DCPG formation from PCCH are considered taking into account (a) differences between stereoisomers in reaction rate and product composition and (b) the observation that a purified soluble GSH-S-transferase (E.C. 2.5.1.18) converted 3,4,6/5PCCH-and a-HCH-to the same set of four isomeric DCPGs as did the entire cytosol fraction. 9. In corroboration of earlier evidence, transferase activity associated with liver microsomes and mitochondria also converts a-HCH and 3,4,6/5-PCCH each to four positional isomers of DCPG. 10. The result of the study is discussed with reference to earlier work in mammals and in insects and in relation to HCH-biotransformation by rats in vivo. Abbreviations:

Abstract: 1. Pyridine-N-oxides have been identified as metabolites in vitro of several 3-substituted pyridines.2. Factors affecting the metabolism of these pyridines in vitro have been studied, and conditions which give the most metabolism have been established.3. ‘Pyridine-N-oxidase' activity resides mainly in the hepatic and pulmonary microsomal fractions.4. A species difference was evident with ‘pyridine-N-oxidase' activity decreasing in the order hamster, rabbit, mouse, guinea-pig and rat.5. A sex difference in ‘pyridine-N-oxidase' activity was also established in rats and mice.6. The appropriate kinetic factors, Km and Vmax, for the N-oxidation of pyridine, 3-methylpyridine and 3-chloropyridine are reported.

Abstract: 1. A radiometric assay for the total metabolism of antipyrine in vitro by hepatic microsomal preparations has been developed.2. Apparent Km and V values for the process were determined in rats, rabbits and in a marsupial (the quokka; Setonix brachyurus). Km values were similar in rats and rabbits (3·5 and 5 mM respectively) but were somewhat lower in quokkas (1·4-1·5 mM). Estimates of V ranged from 49-64 nmol/mg microsomal protein/10 min and were similar in all three species. Pretreatment of rabbits with phenobarbitone significantly increased V without change in Km.3. Studies in individual rabbits and quokkas showed a good corrolation between rate of hepatic microsomal metabolism of antipyrine in vitro and its half-life in vivo.

Abstract: 1. In urine of rats given vinylbital (5-vinyl-5-(1'-methylbutyl)barbituric acid) i.p., unchanged vinylbital and its devinylated metabolite, 5-(1'-methylbutyl)barbituric acid, were identified. Rats synthetic 1',2'-epoxyvinylbital excreted the same compound as a major metabolite. No unchanged epoxide, nor 1',2'-dihydroxyvinylbital, could be identified in the urine of rats treated with vinylbital or its epoxide. 2. Attempts to synthesize 1',2'-dihydroxyvinylbital from 1',2'-epoxyvinylbital by acidic hydrolysis revealed that this possible metabolite decomposes readily to 5-(1'-methylbutyl)barbituric acid by a 'retro-aldol type' reaction. 3. In rat liver microsomal preparation 1',2'-epoxyvinylbital is readily hydrated by epoxide hydratase, but this reaction is almost completely inhibited by 0.8 mM 1,1,1-trichloropropene-2,3-oxide (TCPO). This finding and the identification of 5-(1'-methylbutyl)barbituric acid as end-product of this enzyme reaction provides further evidence for the existence of an epoxide-diol pathway in the metabolism of vinylbital. 4. Vinylbital and its devinylated metabolite are excreted in 36 h urine of rats treated with vinylbital, to an extent of 0.6 +/- 1.7% of the dose (n = 5), respectively. Upon administration of 1',2-epoxyvinylbital, 59.8 +/- 14.2% of the dose (n = 5) was excreted as 5-(1'-methylbutyl)barbituric acid. 5. In 60 h urine of three human volunteers who had taken 150 mg of vinylbital orally, 2.6 +/- 1.7% of the dose was excreted as vinylbitaland 11.0 +/- 4.1% as 5-(1'-methylbutyl) barbituric acid, illustrating that also in humans the epoxide-diol pathway plays a role in the metabolism of vinylbital.

Abstract: 1. The effects of arachidonic acid on hepatic drug-metabolizing enzymes was investigated in male ICR-Swiss mice.2. A single administration of arachidonic acid, 100 mg kg i.p., doubled the hexobarbital sleeping time. Arachidonic acid in vitro gare a type I binding spectrum with hepatic microsomes; it inhibited the metabolism of hexobarbital and of ethylmorphine, two type I binding drugs, but not that of aniline, a type II binding drug; the inhibition of hexobarbital metabolism by arachidonic acid was competitive.3. Repeated administration of arachidonic acid up to a total dose of 1000mg kg i.p., either in the course of 5 hours, or in the course of 5 days, decreased microsomal cytochrome P-450 levels and NADPH—cytochrome c reductase activity.4. It is concluded that the administration of arachidonic acid may impair drug metabolism in two ways, mainly, by competitively inhibiting the activity of drugmetabolizing enzymes, and secondarily, by decreasing the hepatic concentration of these enzymes.

Abstract: 1. The metabolism of ethoxyquin (6-ethoxy-2,2,4-trimethyl-1, 2-dihydroquinoline) in rat has been investigated. Urinary metabolites were identified by combined g.l.c.-mass spectrometry.2. The major metabolic reaction was de-ethylation which gave rise to 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline and an oxidation product, 2,2,4-trimethyl-6-quinolone. Other reactions were hydroxylation to four different hydroxylated metabolites and one dihydroxylated metabolite. A total of 95% of the dose (100mg/kg) was accounted for.

Abstract: 1. Microsomal fractions were prepared from 15-50 g specimens of human lung tissue (mostly alveolar) obtained at surgical resections of 13 middle-aged male patients suffering from different pulmonary tumours. Marker enzyme assays indicated that the fractions contained about 25% of the endoplasmic reticulum of the homogenate and about 10% of its mitochondrial membranes.2. The content of cytochrome b5 corresponded to that of rodent lung microsomes, whereas the apparent content of cytochrome P-450 was much lower.3. The extent of benzo(a)pyrene metabolism varied 13-fold between individuals in the group and was not detectable in about 40% of the cases.4. The dihydrodiols as % of total metabolites formed was higher than in laboratory animals, the 7,8-dihydrodiol in most cases amounting to more than 40% of total dihydrodiols.5. The apparent rate of hydroxylation was stimulated by 1 mM 2-diethylaminothyl 2,2-diphenylvalerate and by 1 mM 1,2-oxy-3,3,3-trichloropropane, but inhibited moderately by 0.1 mM metyrapone ...

Abstract: 1. In urine of rats given vinylbital (5-vinyl-5-(1'-methylbutyl)barbituric acid) i.p., unchanged vinylbital and its devinylated metabolite, 5-(1'-methylbutyl)barbituric acid, were identified. Rats synthetic 1',2'-epoxyvinylbital excreted the same compound as a major metabolite. No unchanged epoxide, nor 1',2'-dihydroxyvinylbital, could be identified in the urine of rats treated with vinylbital or its epoxide. 2. Attempts to synthesize 1',2'-dihydroxyvinylbital from 1',2'-epoxyvinylbital by acidic hydrolysis revealed that this possible metabolite decomposes readily to 5-(1'-methylbutyl)barbituric acid by a 'retro-aldol type' reaction. 3. In rat liver microsomal preparation 1',2'-epoxyvinylbital is readily hydrated by epoxide hydratase, but this reaction is almost completely inhibited by 0.8 mM 1,1,1-trichloropropene-2,3-oxide (TCPO). This finding and the identification of 5-(1'-methylbutyl)barbituric acid as end-product of this enzyme reaction provides further evidence for the existence of an epoxide-diol pathway in the metabolism of vinylbital. 4. Vinylbital and its devinylated metabolite are excreted in 36 h urine of rats treated with vinylbital, to an extent of 0.6 +/- 1.7% of the dose (n = 5), respectively. Upon administration of 1',2-epoxyvinylbital, 59.8 +/- 14.2% of the dose (n = 5) was excreted as 5-(1'-methylbutyl)barbituric acid. 5. In 60 h urine of three human volunteers who had taken 150 mg of vinylbital orally, 2.6 +/- 1.7% of the dose was excreted as vinylbitaland 11.0 +/- 4.1% as 5-(1'-methylbutyl) barbituric acid, illustrating that also in humans the epoxide-diol pathway plays a role in the metabolism of vinylbital.

Abstract: 1. 3-Hydroxypropylmercapturic acid has been identified in the urine of rats dosed with cyclophosphamide, isophosphamide, and trilophosphamide and was isolated as its dicyclohexylammonium salt from the urine of rats dosed with cyclophosphamide.2. Rats excreted in their urine 55·5% of the 14C of an i.p. dose (200 mg/kg) of [4-14C]cyclophosphamide during the first 24 h after administration, and a further 6·6% during the subsequent 24 h. Of the total radioactivity excreted during the first 24 h, unchanged cyclophosphamide represented 19·3% or less, 41·6% was due to the major metabolite, carboxyphosphamide, and 3-hydroxypropylmercapturic acid represented 11·9%. The 14C label in the mercapturic acid was located in the S-substituent.3. 3-Hydroxypropylmercapturic acid was the only sulphur-containing metabolite of cyclophosphamide found in the blood and liver of rats, but 3-hydroxy[14C]propylmercapturic acid and S-(3-hydroxy[14C]propyl)-L-cysteine were tentatively identified in the bile of a rat dosed with [14C]cy...

Abstract: 1. The metabolism of [3H]norcocaine, N-hydroxy[3H]norcocaine and cocaine-N-oxide has been investigated in rats after i.v. injection. 2. The biological t 1/2 of norcocaine (dose 2 mg/kg i.v.) in plasma, liver and brain were 0.4, 1.6, 0.5 h, respectively and the compound was not detectable in the central nervous system 6 h after injection. The % dose of norcocaine excreted unchanged in urine and faeces in 96 h were 0.7 and 1.0, respectively. Benzoylnorecgonine, norecgonine, norecgonine methyl ester and an unidentified compound were excreted in urine. 3. The biological t 1/2 of N-hydroxynorcocaine (5 mg/kg i.v.) in brain and plasma were 0.3, 1.6 h respectively and only 1.3 and 1.6% of dose were excreted unchanged in urine and faeces in 96 h. N-Hydroxybenzoylnorecgonine and N-hydroxynorecgonine methyl ester were the major urinary metabolites. N-hydroxynorcocaine was not metabolized to norcocaine in vitro by liver microsomes. Doses of greater than 7.5 mg/kg i.v. resulted in death of rats by cardiorespiratory arrest. 4. Cocaine-N-oxide (50 mg/kg i.v.) yielded ecgonine-N-oxide methyl ester as its major metabolite; other minor metabolites were cocaine (0.5%), norcocaine (1%), benzoylecgonine, ecgonine, ecgonine-N-oxide, along with minor amounts of unmetabolized compound. Lethality of cocaine-N-oxide (100 mg/kg i.v.) was possibly due to metabolism to norcocaine and cocaine.

Abstract: 1. Peak radioactivity in the blood was reached at 30 min after i.p. and 1 h after oral dosing of [14C]triazolam to rats. In dogs, peak blood level was observed at 30 min after oral dosing. 2. Daily dosing of triazolam to male rats for 21 days caused a gradual increase in blood level, with peak at 1 h after dosing. 3. The rate of binding of triazolam plus its metabolites to plasma protein of rats was about 30% at 15 min and 6 h. 4. In rats, the majority of the activity of the intra-intestinally administered [14C]triazolam was found in the small intestines in 6 h. 5. About 58% of the oral dose and 77% of the i.p. dose were recovered in the bile of rats in 48 h after dosing. When the bile from one rat was introduced into the duodenum of a second rat, approximately 37% was recovered in the bile of the second animal in 24 h. 6. In male rats, high radioactivity was seen in the liver, kidneys, adrenals and heart, and low in the CNS. By 96 h after dosing, radioactivity in the liver, blood and kidneys was very low, and was undetectable in other tissues and organs. Radioactivity levels in tissues after daily dosing for 7, 14 and 21 days did not differ appreciably from single administration. 7. In monkeys, activity was high in the liver, kidneys and skin following oral administration and low in the CNS. 8. After oral administration of [14C]triazolam to pregnant rats, the activity in the uterus and placenta was higher than that in the maternal blood. The activity in the foetus was low. 9. In rats given [14C]triazolam orally or i.p., 85% and 12% of the oral dose, and 82% and 14% of the i.p. dose were recovered in the faeces and urine, respectively, in 96 h. The rate of cumulative faecal and urinary excretion after repeated dosing was similar to the single dosing with 80% and 14% of the activity recovered, respectively, in faeces and urine in 6 days. In dogs, 50% of the oral dose was found in the faeces and 40% in the urine. 10. Radioactivity in the milk of rats was maximal at 4 h after oral dosing. It declined to 34% of the peak level 48 h later.