The Metabolism of Tolamolol* in the Mouse,Rat, Guinea-pig,Rabbit and Dog

1. [³H, ¹⁴C]Tolamolol was well absorbed after oral administration to mice, rats, guinea-pigs, rabbits and dogs.

2. The major route for excretion of. radioactivity by mice, rats and guineapigs was the faeces; in rabbits the major route was the urine. Dogs excreted similar amounts of radioactivity by both routes. Biliary excretion of radioactivity by the rat and guineapig was demonstrated.

3. Tolamolol was extensively metabolized by all five species. The major metabolite in mice, rats, guinea-pigs and rabbits was the product of hydroxylation of the tolyl ring, which was excreted as such and as the glucuronide and sulphate conjugates.

4. In the dog the major metabolite was the acid resulting from hydrolysis of the carbamoyl group. This acid was also excreted by the rabbit, but was only a minor metabolite in the other species studied.     

Metabolism of 6-Chloro-5-cyclohexylindane-1-carboxylic Acid (TAI-284), a New Non-steroidal Anti-inflammatory Agent. III. Species Differences in Metabolism

Abstract

1. After oral administration, the plasma concn. of TAI-284 reached a peak at 1 h (t_0·5 of 3·5 h) in mice, at 2 h (t_0·5 5 h) in rabbits and at 24 h (t_0·5 4·5 days) in guinea-pigs.

2. In mice and rabbits the major plasma metabolite was the pharmacologically active III (trans-4′-ol), but in guinea-pigs more than 97% of plasma radioactivity was accounted for by unchanged drug. Fraction II, containing an ulcerogenic metabolite, IIb (cis-3′-ol), was found in rat plasma but was not detected in the other 3 species.

3. In mice and rabbits, elimination of ingested radioactivity was completed in 72 h, while with guinea-pigs half the dose remained unexcreted at this time. In rats and mice, excretion in urine and faeces was almost equal, whereas in guinea-pigs and rabbits, more was excreted in urine than in faeces. The major urinary metabolites were the unidentified V and VI in rats and mice and metabolite III in guinea-pigs and rabbits.

4. Studies using liver homogenates or isolated liver profusion system demonstrated that limited hepatic entry of TAI-284 and lower enzyme activity were responsible for the slower metabolism in guinea-pigs.     

Comparative disposition and metabolism of 1,2,3-trichloropropane in rats and mice.

1,2,3-Trichloropropane (TCP) has been used as a solvent and degreasing agent and as an intermediate in pesticide manufacture. TCP is currently the subject of a National Toxicology Program chronic toxicity study. The present study is part of a larger effort to characterize the toxicity of TCP. Following acute oral exposure of male and female F344 rats (30 mg/kg) and male B6C3F1 mice (30 and 60 mg/kg), TCP was rapidly absorbed, metabolized, and excreted. The major route of excretion of TCP was in the urine. By 60 hr postdosing, rats had excreted 50% and mice 65% of the administered dose by this route. Exhalation as 14CO2 and excretion in the feces each accounted for 20% of the total dose in 60 hr rats and 20 and 15%, respectively, in mice. No apparent sex-related differences were observed in the ability of the rats to excrete TCP-derived radioactivity. At 60 hr, TCP-derived radioactivity was most concentrated in the liver, kidney, and forestomach in both rats and male mice. Male mice eliminated TCP-derived radioactivity more rapidly than rats and lower concentrations of radioactivity were found in tissues 60 hr after dosing in mice. Two urinary metabolites were isolated and identified by NMR, mass spectroscopy, and comparison with synthetic standards, as N-acetyl- and S-(3-chloro-2-hydroxypropyl)cysteine. Analyses of the early urine (0-6 hr) showed this mercapturic acid to be the major metabolite in rat urine and was only a minor component in mouse urine. 2-(S-Glutathionyl)malonic acid was identified by NMR and mass spectrometry and by chemical synthesis as the major biliary metabolite in rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

The metabolic disposition of C-labelled Ponceau 4R in the rat, mouse and guinea-pig

The absorption, metabolism and excretion of ¹⁴C-labelled Ponceau 4R has been studied in the rat, mouse and guinea-pig. Following administration of a single oral dose of 0·5 or 50 mg/kg body weight substantially all of the dose was excreted in the urine and faeces within 72 hr, with the majority being accounted for in the faeces. In all three species, naphthionic acid was the major urinary metabolite, whereas in the faeces naphthionic acid, 7-hydroxy-8-aminonaphthalene-1,3-disulphonic acid and unchanged dye were found. Pretreating male rats with unlabelled Ponceau 4R in the diet (50 mg/kg/day) for 28 days prior to dosing with the ¹⁴C-labelled colouring had no effect on the route of excretion or the time taken to eliminate the majority of the label. Following a single dose of ¹⁴C-labelled colouring to previously untreated rats, mice and guinea-pigs or to rats pretreated as above, no marked accumulation of radioactivity in any tissue was found, although tissue levels of radioactivity at 72 hr after dosing were higher in the pretreated rats than in those that were not pretreated. Pregnant rats eliminated a single oral dose of ¹⁴C-Iabelled colouring at a similar rate to non-pregnant females; however, some retention of radioactivity in the foetuses was found. In studies of absorption from isolated loops of small intestine containing 50, 500 or 5000 ppm Ponceau 4R, no significant absorption was detected in rats, but some absorption was seen in mice at the lowest concentration, and in the guinea-pig at the two higher concentrations.     

The metabolic disposition of 14C-labelled Ponceau 4R in the rat,mouse and guinea-pig

The absorption, metabolism and excretion of ¹⁴C-labelled Ponceau 4R has been studied in the rat, mouse and guinea-pig. Following administration of a single oral dose of 0·5 or 50 mg/kg body weight substantially all of the dose was excreted in the urine and faeces within 72 hr, with the majority being accounted for in the faeces. In all three species, naphthionic acid was the major urinary metabolite, whereas in the faeces naphthionic acid, 7-hydroxy-8-aminonaphthalene-1,3-disulphonic acid and unchanged dye were found. Pretreating male rats with unlabelled Ponceau 4R in the diet (50 mg/kg/day) for 28 days prior to dosing with the ¹⁴C-labelled colouring had no effect on the route of excretion or the time taken to eliminate the majority of the label. Following a single dose of ¹⁴C-labelled colouring to previously untreated rats, mice and guinea-pigs or to rats pretreated as above, no marked accumulation of radioactivity in any tissue was found, although tissue levels of radioactivity at 72 hr after dosing were higher in the pretreated rats than in those that were not pretreated. Pregnant rats eliminated a single oral dose of ¹⁴C-Iabelled colouring at a similar rate to non-pregnant females; however, some retention of radioactivity in the foetuses was found. In studies of absorption from isolated loops of small intestine containing 50, 500 or 5000 ppm Ponceau 4R, no significant absorption was detected in rats, but some absorption was seen in mice at the lowest concentration, and in the guinea-pig at the two higher concentrations.     

The metabolism of o-fluoroaniline by rats, rabbits and marmosets

o-Fluoroaniline is rapidly metabolized and excreted in rats, rabbits and marmosets. Following a single oral dose of 14C-fluoroaniline of about 20 mg/kg, more than 80% of the dose is excreted in 0-24 h, the urine being the major route of excretion for all three species. For all three species, 4-amino-3-fluorophenyl is a major metabolite, conjugated at oxygen with either sulphate or glucuronic acid. 4-Acetylamino-3-fluorophenyl sulphate or glucuronide are also significant metabolites. An h.p.l.c. method with electrochemical detection was developed for monitoring exposure of plant workers to o-fluoroaniline, based on 4-amino-3-fluorophenyl sulphate.     

Allyl isothiocyanate: comparative disposition in rats and mice

Allyl isothiocyanate (AITC), the major component of volatile oil of mustard, was recently reported to induce transitional-cell papillomas in the urinary bladder of male Fischer 344 rats, but not in the bladders of female rats or B6C3F1 mice. The present investigation of comparative disposition in both sexes of each species was designed to detect sex or species differences in disposition which might explain susceptibility to AITC toxicity. AITC was readily cleared from all rat and mouse tissues so that within 24 hr after administration less than 5% of the total dose was retained in tissues. The highest concentration of AITC-derived radioactivity was observed in male rat bladder. Clearance of AITC-derived radioactivity by each species was primarily in urine (70 to 80%) and in exhaled air (13 to 15%) with lesser amounts in feces (3 to 5%). Rats excreted one major and four minor metabolites in urine. The major metabolite from rat urine was identified by NMR spectroscopy to be the mercapturic acid N-acetyl-S-(N-allylthiocarbamoyl)-L-cysteine. Mice excreted in urine the same major metabolite identified in rat urine as well as three other major and two minor metabolites. Sex-related variations were observed in the relative amounts of these metabolites. Both species excreted a single metabolite in feces. Metabolism of AITC by male and female rats was similar, but female rats excreted over twice the urine volume of male rats. Results of the present study indicate that excretion of a more concentrated solution of AITC metabolite(s) in urine may account for the toxic effects of AITC on the bladder of male rats.     

Metabolism in vivo of the tropane alkaloid, scopolamine, in several mammalian species.

1. In vivo metabolism of scopolamine was studied in rats, mice, guinea pigs and rabbits. The structures of eight urinary metabolites including unchanged drug were elucidated by mass and nuclear magnetic resonance spectrometry. Determination of these metabolites was achieved by a g.l.c. method using a semi-capillary column. 2. The major metabolites in rats were the three phenolic metabolites, p-hydroxy-, m-hydroxy- and p-hydroxy-m-methoxy-scopolamine. 3. Significant intra-species difference of the metabolism was observed in rabbits. Tropic acid was the major metabolite in two rabbits out of three, while the other rabbit excreted mainly unchanged scopolamine, accompanied by five metabolites. Tropic acid was also the major metabolite in guinea pigs, but was of minor importance in mice. 4. The dehydrated metabolites, aposcopolamine and aponorscopolamine, were abundantly excreted in guinea pigs, moderately in mice, and least in rabbits and rats. 5. Excretion of glucuronide conjugates of scopolamine and norscopolamine were high in mice compared with other species. On the other hand, phenolic metabolites in rat urine; and tropic acid in rabbit and guinea pig urine, were excreted as the free forms. 6. These results indicate that scopolamine metabolism is highly species-specific.     

Metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-] in mice, rats, rabbits, and dogs.

The in vivo metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-], a novel neuromodulator, were investigated in mice, rats, rabbits, and dogs after oral administration of (14)C-RWJ-333369. Plasma, urine, and feces samples were collected, assayed for radioactivity, and profiled for metabolites. In almost all species, the administered radioactive dose was predominantly excreted in urine (>85%) with less than 10% in feces. Excretion of radioactivity was rapid and nearly complete at 96 h after dosing in all species. Unchanged drug excreted in urine was minimal (<2.3% of the administered dose) in all species. The primary metabolic pathways were O-glucuronidation (rabbit > mouse > dog > rat) of RWJ-333369 and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid. The latter metabolite was subsequently metabolized in parallel to 2-chlorophenylglycine and 2-chlorobenzoic acid (combined hydrolytic and oxidative pathways: rat > dog > mouse > rabbit). Other metabolic pathways present in all species included chiral inversion in combination with O-glucuronidation and sulfate conjugation (directly and/or following hydroxylation of RWJ-333369). Species-specific pathways, including N-acetylation of 2-chlorophenylglycine (mice, rats, and dogs) and arene oxidation followed by glutathione conjugation of RWJ-333369 (mice and rats), were more predominant in rodents than in other species. Consistent with human metabolism, multiple metabolic pathways and renal excretion were mainly involved in the elimination of RWJ-333369 and its metabolites in animal species. Unchanged drug was the major plasma circulating drug-related substance in the preclinical species and humans.     

Comparison of celecoxib metabolism and excretion in mouse,rabbit, dog,cynomolgus monkey and rhesus monkey

1. The metabolism and excretion of celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, was investigated in mouse, rabbit,the EM(extensive) and PM(poor metabolizer) dog, and rhesus and cynomolgus monkey. 2. Some sex and species differences were evident in the disposition of celecoxib. After intravenous (i.v.) administration of [¹⁴C]celecoxib, the major route of excretion of radioactivity in all species studied was via the faeces: EM dog (80.0%), PM dog (83.4%), cynomolgus monkey (63.5%), rhesus monkey (83.1%). After oral administration, faeces were the primary route of excretion in rabbit (72.2%) and the male mouse (71.1%), with the remainder of the dose excreted in the urine. After oral administration of [¹⁴C]celecoxib to the female mouse, radioactivity was eliminated equally in urine (45.7%) and faeces (46.7%). 3. Biotransformation of celecoxib occurs primarily by oxidation of the aromatic methyl group to form a hydroxymethyl metabolite, which is further oxidized to the carboxylic acid analogue. 4. An additional phase I metabolite (phenyl ring hydroxylation) and a glucuronide conjugate of the carboxylic acid metabolite was produced by rabbit. 5. The major excretion product in urine and faeces of mouse, rabbit, dog and monkey was the carboxylic acid metabolite of celecoxib.     

Comparison of celecoxib metabolism and excretion in mouse, rabbit, dog, cynomolgus monkey and rhesus monkey

1. The metabolism and excretion of celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, was investigated in mouse, rabbit, the EM (extensive) and PM (poor metabolizer) dog, and rhesus and cynomolgus monkey. 2. Some sex and species differences were evident in the disposition of celecoxib. After intravenous (i.v.) administration of [14C]celecoxib, the major route of excretion of radioactivity in all species studied was via the faeces: EM dog (80.0%), PM dog (83.4%), cynomolgus monkey (63.5%), rhesus monkey (83.1%). After oral administration, faeces were the primary route of excretion in rabbit (72.2%) and the male mouse (71.1%), with the remainder of the dose excreted in the urine. After oral administration of [14C]celecoxib to the female mouse, radioactivity was eliminated equally in urine (45.7%) and faeces (46.7%). 3. Biotransformation of celecoxib occurs primarily by oxidation of the aromatic methyl group to form a hydroxymethyl metabolite, which is further oxidized to the carboxylic acid analogue. 4. An additional phase I metabolite (phenyl ring hydroxylation) and a glucuronide conjugate of the carboxylic acid metabolite was produced by rabbit. 5. The major excretion product in urine and faeces of mouse, rabbit, dog and monkey was the carboxylic acid metabolite of celecoxib.     

Metabolic disposition of C-labelled carmoisine in the rat, mouse and guinea-pig

The absorption, metabolism and excretion of ¹⁴C-labelled carmoisine has been studied in the rat, mouse and guinea-pig. Following administration of a single oral dose of either 0.5 or 50 mg/kg body weight, substantially all of the dose was recovered in the excreta within 72 hr, mainly in the faeces. Although the urinary excretion of radioactivity was similar in the rat and the mouse, the proportion of the radioactivity found in the urine of the guinea-pig was significantly greater than that of the other species at both dose levels. Pretreating male rats with unlabelled colouring in the diet (0.05%, w/w) for 28 days prior to dosing with ¹⁴C-labelled colouring had no effect on the route of excretion or the time taken to eliminate the majority of the labelled dose. Following a single oral dose of ¹⁴C-labelled colouring to previously untreated rats, mice and guinea-pigs or to rats pretreated as above, no marked accumulation of radioactivity in any tissue was found. Pregnant rats eliminated a single oral dose of ¹⁴C-labelled colouring at a similar rate to non-pregnant females, and the concentration of radioactivity in the foetuses was similar to that in the other tissues. Naphthionic acid was the major urinary metabolite in all three species. In the rat and mouse, most of the remaining radioactivity co-chromatographed with 2-amino-1-naphthol-4-sulphonic acid (2-ANS), but in the guinea-pig radioactivity also co-chromatographed with 1,2-naphthoquinone-4-sulphonate (1,2-NQS). Only a trace amount of unchanged carmoisine was detected in the urine of the species examined. Naphthionic acid was also found in the faeces of all three species, but neither carmoisine, 2-ANS or 1,2-NQS was detected. At least five other radioactive metabolites were found in the faecal extracts of all three species, including a substantial amount of a compound with chromatographic properties similar to those of a trace metabolite in the urine. Two of the faecal metabolites were hydrolysed by β-glucuronidase and sulphatase treatment. In studies on the absorption of carmoisine at concentrations of 50, 500 or 5000 ppm from isolated intestinal loops, no significant absorption was detected in the rat, mouse or guinea-pig.     

Sex differences in the metabolism and excretion of nilvadipine, a new dihydropyridine calcium antagonist, in rats

1. The metabolic profiles of nilvadipine in the urine and bile of male and female rats were studied after i.v. dosing with 1 mg/kg of the 14C-labelled compound. 2. Excretion rates of the dosed radioactivity in male and female rats, respectively, in the first 48 h were 84.1% and 59.1% in bile, 12.0% and 36.9% in urine, and 2.5% and 3.6% in faeces. 3. Comparison of biliary and urinary excretion for each radioactive metabolite after dosing with 14C-nilvadipine, showed marked sex-related differences in the excretion routes of several metabolites. In male rats, metabolite M3, having a free 3-carboxyl group on the pyridine ring, was not excreted in urine, but in female rats urinary excretion of M3 accounted for 4.7% of the dose. One reason for the lower urinary excretion of radioactivity by males than by females was that the main metabolite, M3, was not excreted in the urine of the male rats. 4. To clarify the sex difference in the route of excretion of M3, this metabolite (M3) was given i.v. to rats. No excretion of the metabolite was observed in urine of male rats within 24 h but, in marked contrast, 41.5% of the dose was excreted in urine of females in the same period.     

Species differences in the metabolism and excretion of fenclofenac

1. The excretion and metabolism of radiolabelled fenclofenac (2-(2, 4-dichlorophenoxy)phenylacetic acid, Flenac^R) has been studied in five species.

2. In the rat, absorption of oral doses of fenclofenac was virtually complete and elimination occurred mainly by the bile and faeces. The guinea-pig excreted equal amounts of radioactivity in urine and faeces, while in rabbit, baboon and man renal excretion was the more important route.

3. In all species the majority of excreted radioactivity was present as fenclofenac ester glucuronide. Amino acid conjunction with fenclofenac was minimal in all species studied.

4. Mono- and di-hydroxylated metabolites have been detected in urine from guineapig, baboon and man. The major hydroxylated metabolite in baboon urine has been identified as 2-(2,4-dichlorophenoxy)-5′-hydroxyphenylacetic acid.     

Disposition of radiolabeled ifetroban in rats, dogs, monkeys, and humans.

Ifetroban is a potent and selective thromboxane receptor antagonist. This study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of ifetroban after i.v. and oral administrations of [14C]ifetroban or [3H]ifetroban in rats (3 mg/kg), dogs (1 mg/kg), monkeys (1 mg/kg), and humans (50 mg). The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring between 5 and 20 min across species. Plasma terminal elimination half-life was approximately 8 h in rats, approximately 20 h in dogs, approximately 27 h in monkeys, and approximately 22 h in humans. Based on the steady-state volume of distribution, the drug was extensively distributed in tissues. Absolute bioavailability was 25, 35, 23, and 48% in rats, dogs, monkeys, and humans, respectively. Renal excretion was a minor route of elimination in all species, with the majority of the dose being excreted into the feces. After a single oral dose, urinary excretion accounted for 3% of the administered dose in rats and dogs, 14% in monkeys, and 27% in humans, with the remainder excreted in the feces. Extensive biliary excretion was observed in rats with the hydroxylated metabolite at the C-14 position being the major metabolite observed in rat bile. Ifetroban was extensively metabolized after oral administration. Approximately 40 to 50% of the radioactivity in rat and dog plasma was accounted for by parent drug whereas, in humans, approximately 60% of the plasma radioactivity was accounted for by ifetroban acylglucuronide.     

Age-related changes in the disposition of benzyl acetate. A model compound for glycine conjugation

The in vivo metabolism and excretion of benzyl acetate (BA), a model compound for glycine conjugation, was examined in male Fischer 344 rats and C57BL/6N mice. Rats aged 3-4, 9, and 25 months received a single oral dose of either 5 or 500 mg/kg 14C-BA, while male mice aged 2, 13, and 25 months received a single oral dose of 10 mg/kg 14C-BA. Urine and feces were collected for 96 hr. Biliary excretion and plasma elimination were also examined in male Fischer rats after iv administration of 5 mg/kg 14C-BA. In both young and old rats and mice, hippuric acid (HA) was the major urinary metabolite after oral dosing of BA. No significant age-related difference was observed in rats in the urinary elimination of BA-derived radioactivity or in the percentage of the total dose excreted as hippuric acid (approximately 95%). Twenty-five-month old rats excreted a significantly higher percentage of the total dose as benzyl mercapturic acid (approximately 2%) than did 3- to 4-month-old rats (approximately 1%) at the 5 mg dose. Benzyl mercapturic acid excretion in 3- to 4-month-old rats was also increased significantly at 500 mg/kg BA vs. 5 mg/kg BA. Fecal excretion of BA-derived radioactivity declined significantly in 25-month-old rats at both the 5 and 500 mg dose. This decrease was reflected by an age-related decline in biliary excretion and higher plasma levels of BA-derived radioactivity. Examination of plasma metabolites revealed a significantly higher level of HA and benzoyl glucuronide in 25-month rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolism of Femoxetine

Abstract: The metabolism of femoxetine, a serotonin uptake inhibitor, has been investigated in rats, dogs, monkeys, and human subjects using two ¹⁴C-femoxetine compounds with labelling in different positions. The metabolic pathways were oxidation (and glucuronidation) and demethylation, both reactions most probably taking place in the liver. Nearly all femoxetine was metabolised, and the same metabolites were found in urine from all four species. Only a small percentage of the radioactivity excreted in the urine was not identified. Rat and dog excreted more N-oxide than monkey and man, while most of the radioactivity (60–100%) in these two species was excreted as two hydroxy metabolites. The metabolic pattern in monkey and man was very similar. About 50% was excreted in these two species as one metabolite, formed by demethylation of a methoxy group. A demethylation of a N-CH₃ group formed an active metabolite, norfemoxetine. The excretion of this metabolite in urine from man varied from 0 to 18% of the dose between individuals. Most of the radioactivity was excreted with the faeces in rat and dog, while monkey and man excreted most of the radioactivity in urine. This difference in excretion route might be explained by the difference in the metabolic pattern. No dose dependency was observed in any of the three animal species investigated.     

Sex differences in the metabolism and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats

1. The metabolic profiles of nilvadipine in the urine and bile of male and female rats were studied after i.v. dosing with 1?mg/kg of the ¹⁴C-labelled compound.

2. Excretion rates of the dosed radioactivity in male and female rats, respectively, in the first 48?h were 8.41% and 59.1% in bile, 12.0% and 36.9% in urine, and 2.5% and 3.6% in faeces.

3. Comparison of biliary and urinary excretion for each radioactive metabolite after dosing with ¹⁴C-nilvadipine, showed marked sex-related differences in the excretion routes of several metabolites. In male rats, metabolite M3, having a free 3-carboxyl group on the pyridine ring, was not excreted in urine, but in female rats urinary excretion of M3 accounted for 4.7% of the dose. One reason for the lower urinary excretion of radioactivity by males than by females was that the main metabolite, M3, was not excreted in the urine of the male rats.

4. To clarify the sex difference in the route of excretion of M3, this metabolite (M3) was given i.v. to rats. No excretion of the metabolite was observed in urine of male rats within 24?h but, in marked contrast, 41.5% of the dose was excreted in urine of females in the same period.     

Blood level, distribution, metabolite pattern and excretion of [14C]alinidine in mice and rats

Following oral and intravenous administration the absorption, distribution, metabolite pattern and excretion of [14C]alinidine, a drug with specific bradycardic efficacy, was studied in mice and rats. [14C]alinidine was rapidly and extensively absorbed. The distribution of radio-labelled drug over the entire animal body was rapid as indicated by blood level curves as well as by whole body autoradiography. In both species radioactive compounds were eliminated from blood with half-lives ranging from 5.6 h to 7.4 h. More than 50% of the renally excreted radioactivity was a uniform substance behaving in in TLC and HPLC experiments like the drug administered. From rat urine this compound could be identified as [14C]alinidine using mass spectrometry. In mice and rats no definite substance with clonidine-like chromatographic properties was found. Biliary excretion was demonstrated in both species. The renal portion of the total radioactivity elimination was 67.2-70.1% of the dose administered in mice and 68.1-85.1% in rats. Total excretion was 85.1-101.3% of radioactivity given and was complete 3-4 days after [14C]alinidine administration. No significant differences in pharmacokinetic behavior in mice and rats could be found.     

Metabolism profiles and excretion of 14C-aminoglutethimide in several animal species and man

1. Following administration of a single oral dose of 14C-aminoglutethimide to rats, guinea-pigs, rabbits and man, greater than 89% of the dose was excreted in urine and faeces within 72 h; dogs eliminated only 51% in this time. 2. Extensive metabolism occurred in all species, with N-acetylaminoglutethimide being the major metabolite except for dog and man. In the latter two species unchanged drug was the main product excreted. 3. A metabolite, 3-(4-acetamidophenyl)-3-(2-carboxamidoethyl)tetrahydrofuran-2-one, not previously found in human urine, was identified. 4. Chronic administration of aminoglutethimide to rats produced no detectable change in the excretory or metabolite patterns of the drug. However chronic administration of phenobarbitone decreased the urinary excretion of 14C over a 72 h period. 5. Residual (72 h) tissue levels of 14C were less than 1 microgram equivalent of 14C-aminoglutethimide/g tissue in the rat, guinea-pig and rabbit. Dog tissues retained a considerable quantity of 14C at this time.