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.     

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.     

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.     

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.     

Absorption,Metabolism, and Excretion of 2,3:4,5-Bis(2-Butylene) Tetrahydro-2 Furaldehyde (Mgk R11)in the Rat

Abstract

Experiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns following oral administration of [formyl-¹⁴C] 2,3:4,5-bis(2-butylene) tetrahydro-2 furaldehyde (MGK R11).

Ten rats (five males and five females) were used in each of the four experiments. Fasted rats were administered [for-myl-¹⁴C] MGK R11 at a single oral dosage of 65 mg/kg, at a single oral dosage of 1000 mg/kg, and at a daily oral dosage of 65 mg/kg of nonradiolabeled compound for 14 days followed by a single dose of ¹⁴C-labeled compound at 65 mg/kg. Rat blood kinetics were determined in the fourth group following a single oral dose of 65 mg/ kg. Each animal was administered approximately 12–14 μCi of radioactivity.

Urine and feces were collected from all groups at predetermined time intervals. Seven days after dose administration, the rats were euthanized and selected tissues and organs were harvested. Samples of urine, feces, and tissues were subsequently analyzed for ¹⁴C content.

In the blood kinetics study, radioactivity peaked at approximately 30 min in both the males and females, indicating very rapid absorption. The decline of radioactivity from blood followed a biphasic elimination pattern. The first half-life was 1.36 h for males and 1.18 h for females. In the second phase, the half-life was 21 h for males and 26 h for females.

Female rats excreted 67.21-86.85% of the radioactivity in urine and 13.99–28.08% in feces, whereas male rats excreted 50.19–64.37% of the administered radioactivity in urine and 31.43–40.94% in feces. Tissue residues of ¹⁴C ranged between 0.47% and 1.09% of the administered dose. The total mean recovered radioactivity of the administered dose in the four definitive studies ranged between 92% and 101%. No parent compound was detected in the urine.

Three major and one minor metabolite was isolated by high-performance liquid chromatography (HPLC) and identified by gas chromatography/mass spectrometry (GC/MS). One major metabolite was formed by oxidation of the aldehyde moiety to the carboxylic acid. A second metabolite was the glucuronic acid conjugate of the carboxylic acid and the third was formed by reduction of the aldehyde moiety of MGK R11 to an alcohol followed by glucuronic acid conjugation. The minor metabolite was the unconjugated alcohol derivative of MGK R11.

The gender of the animals affected the rate, route of excretion, and metabolic profile. The urinary excretion rate was faster in females than in males and the amount excreted was also greater in female rats.     

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.     

Absorption,Distribution, Metabolism,and Excretion of N-Octylbicycloheptene Dicarboximide (MGK 264) Administered Orally to Rats

Abstract

Experiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns following oral administration of [hexyl-1-¹⁴C] N-octylbicycloheptene dicarboximide (MGK 264).

Ten rats (five males and five females) were used in each of the four experiments. Fasted rats were administered fhexyl-1-¹⁴C] MGK 264 at a single oral dose of 100 mg/kg, at a single oral dose of 1000 mg/kg, and at a daily oral dose of 100 mg/kg of nonradiolabeled compound for 14 days followed by a single dose of ¹⁴C-labeled compound at 100 mg/kg. Rat blood kinetics were determined in the fourth group following a single oral dose of 100 mg/kg. Each animal was administered 18-30 μCi radioactivity.

Urine and feces were collected for all groups at predetermined time intervals. Seven days after dose administration, the rats were euthanized and selected tissues and organs were harvested. Samples of urine, feces, and tissues were subsequently analyzed for ¹⁴C content.

In the blood kinetics study, radioactivity peaked at approximately 4 h for the males and 6 h for the females. The decline of radioactivity from blood followed a monophasic elimination pattern. The half-life of blood radioactivity was approximately 8 h for males and 6 h for females.

Female rats excreted 71.45-73.05% of the radioactivity in urine and 20.87-25.28% in feces, whereas male rats excreted 49.49-63.49% of the administered radioactivity in urine and 31.76-46.67% in feces. Total tissue residues of radioactivity at 7 days ranged from 0.13 to 0.43% of the administered dose for all dosage regimens. The only tissues with ¹⁴C residues consistently higher than that of plasma were the liver, stomach, intestines, and carcass. The total mean recovered radioactivity of the administered dose in the studies ranged between 93.1 and 97.4%. No parent compound was detected in the urine.

Four major metabolites and one minor metabolite were isolated from the urine by high-performance liquid chromatography (HPLC) and identified by gas chromatography/mass spectometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS). The four major metabolites were shown to be carboxylic acids produced by either ω-1 oxidation or β-oxidation of the side chain and oxidation of the norbornene ring double bond. The minor metabolite was the carboxylic acid of the intact norbornene ring.

The gender of the animals affected the rate, route of excretion, and metabolic profile. The urinary excretion rate was faster in females than in males and the amount excreted was also greater in female rats.     

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.     

Species differences in the disposition and metabolism of sulfinpyrazone

1. The disposition and metabolism of sulfinpyrazone have been studied in rats, guineapigs, rabbits, dogs, rhesus monkeys and miniature swine after intravenous administration of 100mg/kg of ¹⁴C-labelled drug.

2. In all species, the integrated plasma concentration (AUC, 0-24h) of total radioactivity was almost completely covered by the sum of the AUC-values of unchanged sulfinpyrazone and six metabolites, i.e. the sulphide, the sulphone, p-hydroxy-sulfinpyrazone, the p-hydroxy-sulphide, the p-hydroxy-sulphone and 4-hydroxy-sulfinpyrazone.

3. Comparison of the plasma level profiles of unchanged sulfinpyrazone and the metabolites revealed pronounced differences between the species. Unchanged sulfinpyrazone was the most prominent compound in plasma of rats, dogs, monkeys and swine, whereas the sulphide metabolite predominated in guinea-pigs. In plasma of rabbits, these two compounds were found in similar amounts.

4. Species with predominant renal excretion of the ¹⁴C dose, i.e. rabbits, dogs and monkeys, eliminated sulfinpyrazone to a high extent unchanged. The renal excretion of the sulphide metabolite was low in all species.

5. Species differences in the biotransformation of sulfinpyrazone explain previously observed differences in inhibitory effect on platelet aggregation. This effect is intensive and long-lasting in species showing high plasma concentrations of the sulphide metabolite.     

Absorption,Excretion and Urinary Metabolic Pattern of 3H-Albuterol Aerosol in Man

1. After inhalation of doses of ³H-albuterol (84 and 220 μg) by humans, plasma radioactivity reached a max. after 2 and 4?h, respectively.

2. About 72% of the inhaled dose was excreted within 24?h in urine and a similar urinary excretion pattern was obtained with both dosages. From the excretion pattern of the unchanged drug in urine a half-life of 3.8?h and an elimination constant of 0.18 h^?1 for albuterol were calc.

3. Approx. 28% dose was excreted as unchanged albuterol, 40% as a major urinary metabolite and 4% as a minor metabolite. The major metabolite could be converted to an albuterol-like compound by acid hydrolysis but not enzymically (Glusulase).

4. These results show that albuterol as an aerosol is readily absorbed, and is excreted mainly in the urine as the free drug and at least two metabolites.     

Absorption,distribution, metabolism and excretion of gemigliptin,a novel dipeptidyl peptidase IV inhibitor,in rats

Abstract

1.?The absorption, distribution, metabolism and excretion of a novel dipeptidyl peptidase IV inhibitor, gemigliptin, were examined following single oral administration of ¹⁴C-labeled gemigliptin to rats.

2.?The ¹⁴C-labeled gemigliptin was rapidly absorbed after oral administration, and its bioavailability was 95.2% (by total radioactivity). Distribution to specific tissues other than the digestive organs was not observed. Within 7 days after oral administration, 43.6% of the administered dose was excreted via urine and 41.2% was excreted via feces. Biliary excretion of the radioactivity was about 17.7% for the first 24?h. After oral administration of gemigliptin to rats, the in vivo metabolism of gemigliptin was investigated with bile, urine, feces, plasma and liver samples.

3.?The major metabolic pathway was hydroxylation, and the major circulating metabolites were a dehydrated metabolite (LC15-0516) and hydroxylated metabolites (LC15-0635 and LC15-0636).     

Distribution,Biotransformation and Excretion of Bupivacaine in the Rat and the Monkey

Abstract

1. Following subcutaneous administration of [pipecolyl-G-³H]bupivacaine, radioactivity was slowly absorbed from the injection site; the absorbed radioactivity was distributed rapidly in all tissues examined.

2. Tissue levels peaked between 0·25 and 1 h, but by 24 h were very low.

3. The monkey excreted 80% of the radioactivity in the urine; in the rat only 50% was excreted by this route and the remainder in the bile.

4. The major metabolite in rat urine was a conjugate of 1-butyl-3′-hydroxy-pipecolo-2′,6′-xylidide. Debutylated bupivacaine was not found in rat urine.

5. In the monkey, the amide hydrolysis product, pipecolic acid, was the major metabolite.

6. Debutylation and hydroxylation of bupivacaine also occurred in the monkey; however, only the 4′-hydroxy metabolite was detected.     

The Metabolism of Vitavax by Rats and Rabbits

Abstract

1. Vitavax (carboxin) administered orally to rats and rabbits leads to the excretion of unchanged Vitavax both in the urine and faeces.

2. The major metabolites excreted in the urine were found to be glucuronides of phenols formed by hydroxylation of the parent compound. Vitavax sulphoxide did not appear to be a metabolite.

3. Administration of ¹⁴C-labelled Vitavax showed radioactivity in the salivary gland, liver, kidney and gastrointestinal tract; the compound did not undergo significant ring scission in vivo.     

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.     

Disposition and metabolism of TAK-438 (vonoprazan fumarate), a novel potassium-competitive acid blocker,in rats and dogs

1.?Following oral administration of [¹⁴C]TAK-438, the radioactivity was rapidly absorbed in rats and dogs. The apparent absorption of the radioactivity was high in both species.

2.?After oral administration of [¹⁴C]TAK-438 to rats, the radioactivity in most tissues reached the maximum at 1-hour post-dose. By 168-hour post-dose, the concentrations of the radioactivity were at very low levels in nearly all the tissues. In addition, TAK-438F was the major component in the stomach, whereas TAK-438F was the minor component in the plasma and other tissues. High accumulation of TAK-438F in the stomach was observed after oral and intravenous administration.

3.?TAK-438F was a minor component in the plasma and excreta in both species. Its oxidative metabolite (M-I) and the glucuronide of a secondary metabolite formed by non-oxidative metabolism of M-I (M-II-G) were the major components in the rat and dog plasma, respectively. The glucuronide of M-I (M-I-G) and M-II-G were the major components in the rat bile and dog urine, respectively, and most components in feces were other unidentified metabolites.

4.?The administered radioactive dose was almost completely recovered. The major route of excretion of the drug-derived radioactivity was via the feces in rats and urine in dogs.     

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 absorption,tissue distribution,and excretion of dodecyldimethylamine oxide (DDAO) in selected animal species and the absorption and excretion of DDAO in man

The absorption tissue distribution, and excretion pattern of [methyl-¹⁴C]DDAO and [1-dodecyl-¹⁴C]DDAO administered orally or cutaneously to rats, mice, and rabbits were investigated. The excretion pattern of radioactivity from [1-dodecyl-¹⁴C]DDAO administered orally and cutaneously to man was also investigated. An oral dose of DDAO is rapidly and extensively absorbed and excreted by rats and man. Peak tissue levels of radioactivity resulting from oral administration of [methyl-¹⁴C]DDAO to rats occur within 1 hr after dosing. Cutaneously administered DDAO is absorbed by man, rats, rabbits, and mice. In man, the rate of DDAO absorption through the skin is at least one order of magnitude less than that observed in rats, mice, and rabbits.     

Species differences in the metabolism of a tricyclic psychotropic agent,SQ 11,290-C

The metabolism of SQ 11,290-¹⁴C (4-[3-(7-chloro-5,11-dihydrodibenz[b,e]-[1,4]-oxazepin-5-yl)propyl]-α,β-¹⁴C₂-1-piperazineethanol, dihydrochloride) was studied in mice, rats, guinea pigs, hamsters, New Zealand White or Dutch rabbits, monkeys and man after po administration. The excretion of SQ 11,290-¹⁴C, its metabolites, or both, was chiefly in the feces (with the exception of hamsters and man). Rats and rabbits of either strain excreted 2–5% of the dose—mice and hamsters excreted 20–42%—as ¹⁴CO₂. Hamsters appeared to excrete radioactivity in a quantitative manner most similar to that observed in man, but the metabolites found in the urine and feces of these 2 species were not similar. The disposition of SQ 11,290-¹⁴C in albino and pigmented rabbits cannot be distinguished on the basis of the excretion of radioactivity, but different metabolites appear to be excreted in the urine. No unchanged SQ 11,290-¹⁴C was detected in the excreta of humans. One percent of the dose or less was present as unchanged SQ 11,290-¹⁴C in the urine of any animal species. In the feces, an average of 2–6% of the dose was excreted by animal species as unchanged SQ 11,290-¹⁴C. Whereas albino rabbits excreted in the feces only 3.6% of the dose as unchanged drug, Dutch rabbits excreted about 16.7% of the dose as unchanged drug. In those human subjects excreting large amounts of radioactivity as ¹⁴CO₂, cleavage or degradation of the side chain, or both, rather than hydroxylation of the ring system as had been found previously in dogs, appeared to be a major metabolic pathway.     

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.