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.     

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 amaranth in the rat, mouse and guinea-pig

The absorption, metabolism and excretion of orally administered ¹⁴C-labelled amaranth has been studied in the rat, mouse and guinea-pig. Following administration of a single oral dose of either 2 or 200 mg/kg, most of the radioactivity was excreted in the urine and faeces in the first 24 hr, and substantially all of the dose was recovered in the excreta within 72 hr. In the rat and mouse, the principal route of excretion was the faeces, whereas in the guinea-pig, urinary excretion accounted for up to 50% of the dose. In the rat and guinea-pig the proportion of the dose excreted in the urine was significantly greater at the lower dose level. No marked accumulation of radioactivity was found in any tissues 72 hr after the administration of the labelled colouring. For all three species most of the radioactivity was shown to be associated with naphthionic acid, with traces of unchanged amaranth and a number of other unidentified metabolites also being detected. In the rat and mouse substantially all of the remaining radioactivity was associated with a single unidentified component. Naphthionic acid was found in the faeces of all three species along with a substantial, but variable, amount of unchanged dye. At least six other radioactive peaks were seen in the chromatograms of faecal extracts; two of these peaks had similar chromatographic properties to the unknown metabolites in the urine, but there was no peak corresponding to 1-amino-2-naphthol-3,6-disulphonic acid (I-ANDSA), previously reported as a urinary metabolite of amaranth. In studies of absorption from isolated loops of small intestine of the rat, mouse and guinea-pig, no significant absorption of amaranth was detected over a 100-fold concentration range (20–2000 ppm).     

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.     

The absorption, metabolism and excretion of disodium cromoglycate in nine animal species

The plasma concentrations and excretion of disodium cromoglycate after iv administration were studied in 9 animal species: mouse, rat, rabbit, dog, silky marmoset, squirrel monkey, Java (cynomolgus) monkey, stump-tailed macaque and baboon. In each species the decline of plasma concentration was rapid and the compound was quickly excreted in the bile and urine. Bile: urine ratios of excreted compound varied, the squirrel monkey excreted most of the dose in the bile (78–88%) whereas the rabbit excreted most of the dose in the urine (74–84%). Other species were intermediate between these two extremes. Tissue residues were low. Poor absorption (1–5%) after oral administration was found. No metabolites were detected in any species.     

Disposition and metabolism of benoxaprofen in laboratory animals and man.

1. The absorption, distribution, metabolism and excretion of benoxaprofen, a novel anti-inflammatory compound, has been studied in the dog, mouse, rat, rabbit, rhesus monkey and man. 2. Benoxaprofen was well absorbed after oral administration of doses of 1 to 10 mg/kg in all six species. Only unchanged drug was detected in plasma. It was extensively bound to plasma proteins, the highest binding occurring in man (99.8%) and rhesus monkey (99.6%). 3. Species differences were observed in the plasma elimination half-life, the longest being in man (33 h). The rat and mouse also had high values (28 and 24 h respectively) whereas in the other species, values were less than 13 h. 4. After an oral dose of [14C]benoxaprofen (20 mg/kg) to female rats, tissue concn. was highest in liver, kidney, lungs, adrenals and ovaries. Tissue distribution in the pregnant rat was identical to the normal female. The compound was found in the foetus but at a concn. lower than in all maternal organs. 5. There was a marked species difference in the route of excretion. In man, rhesus monkey and rabbit, excretion in the urine was a major route, whilst biliary--faecal excretion was the only effective route in the rat and dog. 6. No major metabolic transformation of benoxaprofen was observed. Man and dog excreted the compound predominantly as the ester glucuronide whereas the rat, mouse, rabbit and rhesus monkey excreted a large proportion of the dose unchanged.     

The Disposition and Metabolism of Amodiaquine in Small Mammals

1. 7-Chloro-4-(3′-diethylamino-4′-hydroxyanilino)quinoline (amodiaquine) labelled with ¹⁴C has been synthesized and administered in single doses to rats including bile-duct-cannulated rats, to guinea-pigs and to mice, by oral or parenteral routes.

2. Amodiaquine was extensively and rapidly absorbed from the rat intestinal tract. Excretion of total radioactivity from rats and guinea pigs was slow and prolonged and was <50% dose in 9 days. Excretion of ¹⁴C was predominantly in faeces of rats after oral and i.p. dosage, and guinea-pigs after i.p. dosage. Radioactivity in rat and guinea-pig urine was <11% dose.

3. Biliary excretion of ¹⁴C following oral or i.v. dosage to rats was 21% dose in 24?h.

4. Amodiaquine was extensively metabolized and conjugated with <10% dose excreted unchanged in urine or bile. Two major basic metabolites in rat urine were tentatively identified as the mono- and bis-desethyl amines.

5. 7-Chloro-4-(4′-diethyl-1′-methylbutylamino)quinoline (chloroquine) was excreted largely unchanged in urine of rats after oral or parenteral administration of single doses, with <5% dose excreted in rat bile in 24?h.     

Species variations in the N-oxidation of chlorphentermine

The metabolism and excretion of orally administered or injected [¹⁴C]chlorphentermine has been studied in man, rhesus monkey, marmoset, rabbit, guinea-pig and rat. These species excreted 55–95% of the administered radioactivity in the urine over 5 days. Two metabolites were characterised by thin-layer and paper chromatography, gas-liquid chromatography and g.c.-m.s. and these were N-hydroxychlorphentermine and 1-(4'-chlorophenyl)-2-methyl-2-nitropropane. There are marked species differences in the excretion of N-oxidation products which were found in the urine of human volunteers. rhesus monkeys, rabbits and guinea-pigs, but not in the urine of marmosets or rats. The rat, rabbit and marmoset also excreted an unidentified unstable acid-labile precursor of chlorphentermine. The results are discussed in relation to the toxicity of the drug and to the metabolism of amphetamines in general.     

UDP glucuronyltransferase and phenolsulfotransferase from rat liver in vivo and in vitro—IV: Species differences in harmol conjugation and elimination in bile and urine in vivo

Harmol, (7-hydroxy-1-methyl-9H-pyrido-3,4b)-indol, is converted to harmol-sulfate and harmol-glucuronide when it is injected in vivo in the rat. Conjugation of harmol, and elimination of the conjugates in bile and urine were studied in cat, rabbit, mouse, guinea-pig and rat after an intravenous dose of 20 μmoles/kg. Rabbit and guinea-pig nearly exclusively glucuronidated harmol. The cat predominantly synthesized harmol-sulfate but harmol-glucuronide was also produced. Mouse and rat synthesized both conjugates to comparable amounts. After 2 hr about 20% of the dose was found in urine in the form of the conjugates. From 30–60% of the dose was present in bile after this time; the rabbit excreted only 9% in that time in bile and was a poor excretor in bile. The glucuronide conjugate is excreted to a higher extent in bile than the sulfate conjugate. The data suggest that biliary excretion requires a high liver concentration of the relevant compound for a high rate or excretion.     

4,4′-Dichlorobiphenyl: Distribution,metabolism, and excretion in the dog and the monkey

The tissue distribution, metabolism, and excretion of 4,4′-dichlorobiphenyl (4,4′-DCB) were investigated in beagle dogs and cynomolgus monkeys (Macaca fascicularis). Following a single iv dose of [¹⁴C]4,4′-DCB (0.6 mg/kg) excreta, blood, and tissues were collected at time intervals ranging from 15 min to 28 days for determination of levels of parent compound and its metabolites. Elimination of the parent PCB in the blood of both species was biphasic with a terminal-phase elimination rate constant of 0.018 hr^?1 for the dog and 0.002 hr^?1 for the monkey. By 24 hr the dog excreted 50% of the dose in the feces (43%) and the urine (7%). The percentage dose remaining was found largely as parent compound in the fat with some in muscle and skin. By 5 days 90% of the dose was excreted. In contrast, during the first 24 hr the monkey excreted less than 15% of the dose with less than 1% in the feces. The percentage dose remaining in the body was localized as parent compound in fat (33%) with lesser amounts in skin and muscle. By 28 days 59% of the dose was excreted, primarily in the urine. In anesthetized dogs 33% of the dose was excreted into the bile within 2 hr, while the monkey excreted only 0.4% of the dose by that route. The data present a clear species variation between the dog and the monkey in both the rate and route of excretion of 4,4′-DCB.     

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.     

Some Metabolites of S-Pentyl-L-cysteine in the Rabbit and Other Species

Abstract

1. The metabolism of S-pentyl-L-cysteine has been investigated in the guinea pig, hamster, mouse, rabbit and rat and in vitro by liver slices of these animals and of the pigeon and by kidney slices of mouse, rabbit and rat.

2. The amounts of pentylmercapturic acid, 3-(pentylthio)lactic acid and 3-(pentylthio)pyruvic acid excreted have been measured.

3. All the species examined excreted pentylmercapturic acid, the amount varying from 2% of the dose by the guinea pig to 73% by the hamster. 3-(Pentylthio)pyruvic and 3-(pentylthio)lactic acids were not detected in the urine of the hamster or rat but were excreted by the other species in amounts approximately the same as those of pentylmercapturic acid.

4. ‘Hydroxypentylmercapturic’ acids were excreted by mouse, rabbit and rat and were identified in the case of the rabbit and rat.

5. 4-Carboxybutylmercapturic acid was identified in the urine of dosed mice, rabbits and rats. A further metabolite in rat urine was tentatively identified as 3-(4-carboxybutylthio)lactic acid.

6. Pentylmercapturic acid sulphoxide was detected in the urine of dosed guinea pigs and mice.

7. All tissue preparations examined converted pentyl-L-cysteine to pentylmercapturic acid. 3-(Pentylthio)lactic acid and 3-(pentylthio)pyruvic acid were formed by all tissues examined although only in trace amounts by hamster liver and rat kidney slices. All tissues examined formed hydroxymercapturic acids' although only traces were detected in digests containing hamster liver slices. 4-Carboxybutylmercapturic acid was formed in rabbit liver digests. With rabbit kidney a metabolite thought to be 3-(4-carboxybutylthio)lactic acid was produced.     

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.     

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.     

Some observations on the urinary excretion of glycine conjugates by laboratory animals

1. An isotope dilution assay has been developed for measuring the amount of conjugated glycine present in urine. The average daily excretion of conjugated glycine by male and female mouse, rat, guinea-pig and rabbit has been determined.

2. The glycine conjugates excreted by the four species have been identified. All species excreted only benzoylglycine and phenylacetylglycine.

3. The metabolism of [carboxy-¹⁴C]benzoic acid and [1-¹⁴C]phenylacetic acid has been investigated in the Sprague-Dawley rat. When administered over a range of concn. from 10 μg/kg to 1?g/kg, benzoic acid is converted to hippuric acid while phenylacetic acid is converted to phenylacetylglycine and phenylacetylglutamine.

4. Neither the rate of excretion nor the composition of the urinary metabolites arising from each acid is changed when low doses of one acid are co-administered with a high dose of the other.

5. The origin of the conjugated benzoic and phenylacetic acids is discussed.     

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.     

The biliary excretion of tartrazine. Sex differences in the rat and species differences in the rat,guinea-pig and rabbit

The excretion of tartrazine in the bile and urine has been studied in biliary cannulated rats, rabbits and guinea-pigs. This dye is excreted unchanged by these species. In the rat a sex difference in the relative amounts of tartrazine excreted in bile and urine has been found. Male rats excrete in 3 h about 17 % of an intravenous dose (50 μmol/kg) in the bile and about 70% in the urine, whereas females excrete about 40 and 45 % respectively. The biliary excretion of tartrazine in the rat appears to be influenced by dose level, for at the lower level of 4.5 μmol/kg male rats excrete about 9 % of an intravenous dose in the bile and 64% in the urine in 3 h, the corresponding values for female rats being 30% and 50%. There is also a species difference in the extent of biliary excretion of tartrazine (50 μmol/kg intravenously). The female rat and female guinea-pig excrete in 3 h about 40 % of the dose in the bile and a similar amount in the urine whereas the female rabbit excretes only 6% in the bile and nearly 70% in the urine. Previous work in this laboratory has shown that molecular weight is an important factor in the biliary excretion of foreign compounds and the present results fit in with this view.     

The fate of lysergic acid DI[14C]ethylamide ([14C]LSD) in the rat, guinea pig and rhesus monkey and of [14C]iso-LSD in rat.

The qualitative and quantitative aspects of the metabolism and elimination of [¹⁴C]LSD in the rat, guinea pig and rhesus monkey have been investigated. Rats given an i.p. dose (1 mg/kg) excreted 73% of the ¹⁴C in the faeces, 16% in the urine and 3.4% in the expired air as ¹⁴CO₂ in 96 hr. Guinea pigs similarly dosed, excreted 40% in the faeces, 28% (urine) and 18% (expired ¹⁴CO₂) in 96 hr. Rhesus monkeys (0.15 mg/kg i.m.) eliminated 39% of the ¹⁴C in the urine and 23% in the faeces in 96 hr.Extensive biliary excretion of [¹⁴C]LSD occurred in both the rat and guinea pig. Bile duct-cannulated rats excreted 68% of an i.v. dose (1.33 mg/kg) in the bile in 5 hr and the guinea pig 52% in 6 hr.[¹⁴C]LSD is almost completely metabolised by all three species and little unchanged drug is excreted. The metabolites identified were 13- and 14-hydroxy-LSD and their glucuronic acid conjugates. 2-oxo-LSD. de-ethyl LSD and a naphthostyril derivative. There occur, however, important species differences in the nature and amounts of the various metabolites. In the rat and guinea pig the major metabolites were the glucuronic acid conjugates of 13- and 14-hydroxy-LSD which were found in both urine and bile. The guinea pig excreted significant amounts of 2-oxo-LSD in urine and bile. De-ethyl LSD was a minor urinary metabolite in both species.The metabolism of LSD appeared to be more complicated in the rhesus monkey. The urine contained at least nine metabolites of which four were identified as follows: 13- and 14-hydroxy-LSD (as glucuronic acid conjugates) de-ethyl LSD and a naphthostyril derivative. Unlike the rat and guinea pig the glucuronic acid conjugates of 13- and 14-hydroxy-LSD were only present in small amounts. Of the remaining five unidentified metabolites, three were major.The biliary metabolites of [¹⁴C]iso-LSD in the rat have been studied and been shown to be similar to those produced from [¹⁴C]LSD, namely 13- and 14-hydroxy-iso-LSD and their glucuronic acid conjugates and 2-oxo-iso-LSD.     

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 guinea-pigs 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 guinea-pig 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 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.     

Disposition and urinary metabolic pattern of cabergoline,a potent dopaminergic agonist,in rat,monkey and man

1. The disposition and urinary metabolic pattern of ¹⁴C-cabergoline was studied in rat, monkey and man after oral administration of the labelled drug.

2. In all species radioactivity was mainly excreted in faeces, with urinary excretion accounting for 11, 13 and 22% of the dose in rat, monkey and man, respectively.

3. After oral treatment, biliary excretion of radioactivity in rat accounted for 19% of the dose within 24?h.

4. Unchanged drug in 0-24-h urine samples of rat, monkey and man amounted to 20, 9 and 10% of urinary radioactivity, respectively. In the 24-72-h urine samples of all species the relative percentage of unchanged drug increased compared with that measured in the 0-24-h urine.

5. The main metabolite was the acid derivative (FCE21589), which in 0-24-h urine samples of rat, monkey and man accounted for 30, 21 and 41% of urinary radioactivity, respectively.

6. Other metabolites identified in urine of all species resulted from hydrolysis of the urea moiety, the loss of the 3-dimethylaminopropyl group and the deallylation of the piperidine nitrogen.