The metabolism of the anti-inflammatory drug eterylate in rat, dog and man

Oral doses of 14C-eterylate were well absorbed by rat and man and excreted mainly in the urine (94% dose by rat in three days and 91% by man in five days). Oral doses to dogs were excreted in similar proportions in both the urine and faeces, although faecal 14C was probably derived in part, from biliary-excreted material. Peak plasma 14C and drug concn. were generally reached between one and three hours after oral doses. In humans, only two metabolites, salicylic acid and 4-acetamido-phenoxyacetic acid, were detected in plasma. The latter was cleared more rapidly than the former and hence plasma salicyclate concn. reached a peak (10.9 and 19.8 micrograms/ml in Subjects 1 and 2, respectively) and initially declined with a half-life of about two-three hours. Plasma 4-acetamidophenoxyacetic acid concn. reached a peak (4.3, 10.0 micrograms/ml, respectively) and declined with a half-life of about one hour. Tissue concn. of 14C were generally greater in dogs than in rats. Highest conc. occurred at three hours in dogs and at one hour in rats. Apart from those in the liver and kidneys, tissue concn. were lower than those in the corresponding plasma. Unchanged drug was not detected in urine or plasma of any species and was rapidly metabolized in human plasma. The major 14C components in human urine were identified as salicyluric acid and 4-acetamidophenoxyacetic acid; minor metabolites were salicylic acid, gentisic acid and paracetamol. These metabolites were also detected in rat urine albeit in different proportions to those in human urine. Dog urine contained less of these metabolites and a major proportion of the 14C was associated with relatively non-polar components. Although salicylic acid and 4-acetamidophenoxyacetic acid were the only major circulating metabolites in man and rat, dog plasma also contained the non-polar urine metabolites.     

The metabolism of the anti-inflammatory drug eterylate in rat,dog and man

1. Oral doses of ¹⁴C-eterylate were well absorbed by rat and man and excreted mainly in the urine (94% dose by rat in three days and 91% by man in five days). Oral doses to dogs were excreted in similar proportions in both the urine and faeces, although faecal ¹⁴C was probably derived in part, from biliary-excreted material.

2. Peak plasma ¹⁴C and drug concn. were generally reached between one and three hours after oral doses. In humans, only two metabolites, salicylic acid and 4-acetamido-phenoxyacetic acid, were detected in plasma. The latter was cleared more rapidly than the former and hence plasma salicylate concn. reached a peak (10.9 and 19.8 μg/ml in Subjects 1 and 2, respectively) and initially declined with a half-life of about two-three hours. Plasma 4-acetamidophenoxyacetic acid concn. reached a peak (4.3, 10.0 μg/ml, respectively) and declined with a half-life of about one hour.

3. Tissue concn. of ¹⁴C were generally greater in dogs than in rats. Highest conc. occurred at three hours in dogs and at one hour in rats. Apart from those in the liver and kidneys, tissue concoccurred were lower than those in the corresponding plasma.

4. Unchanged drug was not detected in urine or plasma of any species and was rapidly metabolized in human plasma. The major ¹⁴C components in human urine were identified as salicyluric acid and 4-acetamidophenoxyacetic acid; minor metabolites were salicylic acid, gentisic acid and paracetamol. These metabolites were also detected in rat urine albeit in different proportions to those in human urine. Dog urine contained less of these metabolites and a major proportion of the ¹⁴C was associated with relatively non-polar components. Although salicylic acid and 4-acetamidophenoxyacetic acid were the only major circulating metabolites in man and rat, dog plasma also contained the non-polar urine metabolites.     

Metabolism of captopril-L-cysteine,a captopril metabolite,in rats and dogs

1. The metabolism of [¹⁴C]captopril-L-cysteine was studied in spontaneously hypertensive rats and pure-bred beagles after a single i.v. dose (4?mg/kg).

2. During the first 24?h, concn. of total radioactivity in blood were similar in both species.

3. Captopril was found in small amounts in the blood of both species. In rats, captopril, bound covalently but reversibly to plasma proteins (CP-PR), was the major component in blood (70%), whereas captopril-L-cysteine was a minor component (23%) of the total radioactivity. In dog blood, CP-PR constituted a smaller fraction (45%) of the total radioactivity than in the rat and captopril-L-cysteine was the major component (53%).

4. In 72?h, 89–91% of the dose was excreted in the urine of rats and dogs. Captopril-L-cysteine accounted for 7% (rat) and 68% (dog) of the radioactivity in urine; captopril accounted for 75% (rat) and 7% (dog). Other metabolites were present in the urine of both species.

5. The greater net conversion of captopril-L-cysteine to CP-PR and to captopril in rats helps explain why captopril-L-cysteine is excreted in urine as a major metabolite of captopril in dogs but only a minor one in rats.     

The Metabolic Fate of the Coronary Dilator 4-(3,4,5-Trimethoxycinnamoyl)-1-(N-Isopropylcarbamoylmethyl)- Piperazine in the Rat,Dog and Man

1. An oral dose of the coronary dilator 4-(3,4,5-trimethoxycinnamoyl)-1- (N-isopropylcarbamoylmethyl)-piperazine was readily absorbed and more than 75% of the dose was excreted within 24 h by the rat, dog and man. In 4 days, rat, dog and man excreted in the urine and faeces respectively 32.5 and 62.3%, 43.9 and 49.1%, and 57.8 and 43.3%. Faecal radioactivity was mainly excreted via the bile.

2. Plasma concentrations of radioactivity reached a maximum within 1 h in rats and dogs and within 2 h in man. For several h, more than 50% of the radioactivity circulating in the plasma of rats and more than 80% in man was due to unchanged drug.

3. Sequential whole-body autoradiography of the rat indicated that much of the radioactivity was distributed in the liver, kidneys and gastrointestinal tract and that there was significant uptake into the heart and lungs.

4. Although similar metabolites were excreted by the rat, dog and man, the relative proportions differed. 11.7, 2.3 and 28.8% respectively of the unchanged drug were excreted in the urine and 13.1, 19.5 and 10.4% respectively of the principal metabolite a glucuronide whose exact structure was not determined. Other metabolites included 4-(3,4,5-trimethoxycinnamoyl)-1-carbamoylmethyl piperazine and N-(3,4,5-trimethoxycinnamoyl)-piperazine.     

Metabolism of the anti-psoriatic agent 5-methoxypsoralen in humans: comparison with rat and dog.

1. Single oral doses of 14C-5-methoxypsoralen (5-MOP) to human subjects (50 mg), rats (1 mg/kg) and dogs (1 mg/kg) were fairly well absorbed but subjected to extensive first-pass metabolism, at least in rat and human. Means of 62, 51 and 40% dose in urine and 31, 38 and 48% dose in faeces, were excreted by humans (during 5 days), rats (3 days) and dogs (1 day), respectively. In dogs, faecal 14C was probably derived, in part, from biliary excreted material. 2. Total 14C in human plasma reached peak concentrations after 2 h (mean 235 ng 5-MOP equivalent/ml) and declined relatively slowly, to about 60% of this value within 24 h. Unchanged 5-MOP was not detected in plasma using h.p.l.c. (< 5 ng/ml). 3. Tissue concentrations of 14C were generally greater in dogs than rats and reached peak levels at 1 h in dogs but at 24 h in rats. Apart from liver and bile, dog tissue 14C concentrations were lower than those in the corresponding plasma, whereas in rat they were lower only until the time of peak concentrations, after which they were generally greater. 4. 5-MOP was extensively metabolized in all three species. The major 14C-components in human and dog urine were glucuronic acid conjugates, mainly of an arylacetic acid and arylalcohols, resulting from initial oxidative metabolism of the furan ring of 5-MOP. In rat, these metabolites were excreted mainly unconjugated. An unusual metabolite was formed by reduction of the lactone moiety of 5-MOP, probably by the gut flora, giving rise to an arylpropionic acid, excreted as a glucuronic acid conjugate in the urine of all three species. 5. Unchanged drug was a very minor component of human and rat plasma, but a major component of dog plasma. In all three species, circulating 14C-metabolites were similar to those in the urine but were present mainly unconjugated. On the basis of these data, the metabolic fate of 5-MOP in humans was more similar to that in dog than to that in rat, although humans appeared to metabolize 5-MOP more rapidly than did dog.     

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.     

Identification of ibopamine metabolites in rat and dog urine

Metabolism of ibopamine (N-methyldopamine-O,O'-diisobutyryl ester) was studied in rats and dogs. The compound was well absorbed in both species when given orally. Most of the administered radiolabel (74-94%) was excreted within 24 hr in urine of both species. The major metabolite in rat urine was 4-glucuronylepinine (63% of the total administered dose). Minor metabolites identified were 4-O-glucuronyl-3-O-methylepinine, 3,4-dihydroxyphenylacetic acid (DOPAC), DOPAC-glucuronide, homovanillic acid (HVA), and HVA-glucuronide. Free epinine and epinine sulfate were detected in the range of less than 1% of the total administered dose. Metabolite patterns in dog urine were different from those of rat urine. The major metabolite was epinine-3-O-sulfate (62% of the total administered dose). Minor metabolites identified in dog urine were DOPAC-sulfate, HVA-sulfate, and free HVA. Free epinine was detected but in the range of less than 1% of the total administered dose. These results showed that ibopamine underwent extensive hydrolysis in vivo to epinine, which was subsequently conjugated and excreted as major metabolites in urine. In addition, side chain degradation of epinine led to minor metabolites, which were excreted in urine as free and conjugated forms. The route of conjugation of ibopamine metabolites is species dependent.     

Biotransformation of lofexidine in humans

1. Concentrations of unchanged drug and patterns of radioactive components in urine have been determined by h.p.l.c. following single oral doses of [14C]lofexidine hydrochloride (0.32 mg) to six human subjects. 2. A mean of 12% of the administered dose was excreted in urine as unchanged lofexidine, but the wide range (5-20% dose) indicated significant intersubject variation in the extent of biotransformation. This drug would appear to be metabolized more extensively than the related anti-hypertensive agent, clonidine. 3. The principal metabolite of lofexidine was 2,6-dichlorophenol, which was apparently excreted in urine as two O-glucuronic acid conjugates. The same two metabolites were also the main 14C components circulating in plasma at peak 14C concn. Formation of the phenol from lofexidine probably involved direct O-dealkylation rather than stepwise degradation of the side-chain. 4. Patterns of 3H components in the urine of rats and dogs after oral administration of [3H]lofexidine hydrochloride (0.1 mg/kg) were generally similar to those in human urine.     

Species differences in the metabolism of suprofen in laboratory animals and man

The metabolism of the oral anti-inflammatory agent suprofen (S), 2-4-(2-thienylcarbonyl)phenyl)propionic acid, has been studied in mice, rats, guinea pigs, dogs, monkeys, and human volunteers. The major metabolites of S in the serum, urine, and feces of these species were determined by GC/MS and HPLC techniques. The metabolic pathways of S in these species involved reduction of the ketone group to an alcohol (S-OH), hydroxylation of the thiophene ring (T-OH), elimination of the thiophene ring to a dicarboxylic acid (S-COOH), and conjugation with glucuronic acid or taurine. In 72-hr urine and feces of these species after po dosing of 1.6 to 2 mg/kg of S, S and these metabolites accounted for 46 to 92% of the dose and were mainly excreted in the urine. S was present as a major product (excreted mainly in conjugated form) in all species. S-OH was a major component in guinea pig and dog but a minor one in other species. T-OH was identified as a major metabolite in monkey, rat, mouse, and man, but a minor one in guinea pig, and it was absent in the dog. S-COOH was present as the minor metabolite in mouse and rat, and present at trace levels in dog, monkey, and man. Conjugation of the propionic acid functionality with taurine was observed only in the dog; in the other species, conjugation with glucuronic acid was extensive. Absorption parameters of S in the rat and monkey were similar to those in man; however, other species were very different from man.     

Disposition of 8-methyl-8-azabicyclo[3,2,1]octan-3-yl 3,5-dichlorobenzoate, a potent 5-hydroxytryptamine antagonist, and two metabolites in dogs and monkeys.

The disposition of 8-methyl-8-azabicyclo[3,2,1]octan-3-yl 3,5-dichlorobenzoate (MDL 72,222; 1), a potent 5-hydroxytryptamine antagonist, and its N-demethylated and N-oxide metabolites was studied in dogs and monkeys. After single, intravenous doses of 1 at 5 mg/kg, the mean terminal half-lives of 1 in plasma were 2.6 h in the dog and 3.8 h in the monkey. The mean half-life of the N-demethylated metabolite in dogs (approximately 20 h) was very similar to that in monkeys. However, the mean half-life of the N-oxide metabolite in dogs (10.8 h) was different from that in monkeys (3.9 h). The steady-state volume of distribution of 1 was 16 L/kg in dogs and 8.9 L/kg in monkeys. Examination of the mean residence times revealed that 1, in both species, and the N-oxide metabolite, in dogs, distributed to the peripheral tissue, whereas the distribution of the N-demethylated metabolite in both species and the N-oxide metabolite in monkeys was limited mainly to the systemic circulation. Compound 1 was metabolized extensively in both species. In dogs, 0.7, 2.5 and 40.6% of the administered dose were excreted in 0-120-h urine samples as 1 and its N-demethylated and N-oxide metabolites, respectively. In monkeys, however, the corresponding percentages were 0.8, 0.7, and 1.8%. Most of the administered dose in monkeys was excreted in urine as 3,5-dichlorobenzoic acid and its glycine conjugate.     

The metabolism of 14C-tazadolene succinate in the dog.

1. Beagle dogs dosed orally with 14C-tazadolene succinate excreted much of the dose in the urine (mean 63.1% in 5 days with most excreted in the first 24 h). A lesser proportion of the dose was excreted in the faeces (mean 20.7%) and again most of this was voided in the first 24 h. 2. Four metabolites were identified and quantified in the urine, namely 3-hydroxy-(M1), 4-hydroxy- (M2a), and 3-methoxy-4-hydroxy-tazadolene (M2b) and N-[2-(phenylmethylene)cyclohexyl]-beta-alanine (M3). 3. In the 24 h urine, M2a and b glucuronides accounted for 17.7% dose, unconjugated M2a and b for 11.3%, and M3 for 18.3%. Insufficient M1 was present to be quantified. The same metabolites were seen in the 24 h faeces, but at lower concn. Thus M2a and b glucuronides, M2a and b, and M3 were 3.2%, 4.9% and 3.5% dose respectively. 4. All three phenols were present in plasma as their glucuronides as well as the beta-alanine derivative. They all had the same tmax of 2 h and t1/2 lambda 1 of the order of 1 h.     

Metabolism of the anti-psoriatic agent 5-methoxypsoralen in humans: comparison with rat and dog

1. Single oral doses of ₁₄C-5-methoxypsoralen (5-MOP) to human subjects (50 mg), rats (1 mg/kg) and dogs (1 mg/kg) were fairly well absorbed but subjected to extensive first-pass metabolism, at least in rat and human. Means of 62, 51 and 40% dose in urine and 31, 38 and 48% dose in faeces, were excreted by humans (during 5 days), rats (3 days) and dogs (1 day), respectively. In dogs, faecal ₁₄C was probably derived, in part, from biliary excreted material.

2. Total ₁₄C in human plasma reached peak concentrations after 2 h (mean 235 ng 5-MOP equivalent/ml) and declined relatively slowly, to about 60% of this value within 24 h. Unchanged 5-MOP was not detected in plasma using h.p.l.c. (< 5 ng/ml).

3. Tissue concentrations of ₁₄C were generally greater in dogs than rats and reached peak levels at 1 h in dogs but at 24 h in rats. Apart from liver and bile, dog tissue ₁₄C concentrations were lower than those in the corresponding plasma, whereas in rat they were lower only until the time of peak concentrations, after which they were generally greater.

4. 5-MOP was extensively metabolized in all three species. The major ₁₄C-components in human and dog urine were glucuronic acid conjugates, mainly of an arylacetic acid and arylalcohols, resulting from initial oxidative metabolism of the furan ring of 5-MOP. In rat, these metabolites were excreted mainly unconjugated. An unusual metabolite was formed by reduction of the lactone moiety of 5-MOP, probably by the gut flora, giving rise to an arylpropionic acid, excreted as a glucuronic acid conjugate in the urine of all three species.

5. Unchanged drug was a very minor component of human and rat plasma, but a major component of dog plasma. In all three species, circulating ₁₄C-metabolites were similar to those in the urine but were present mainly unconjugated. On the basis of these data, the metabolic fate of 5-MOP in humans was more similar to that in dog than to that in rat, although humans appeared to metabolize 5-MOP more rapidly than did dog.     

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.     

Identification and measurement of urinary metabolites of afloqualone in man

Major urinary metabolites in man of 6-amino-2-fluoromethyl-3-(o-tolyl)-4-(3H)-quinazolinone (afloqualone, I), a new centrally acting muscle relaxant, were identified by GC/MS. Simultaneous quantitative determination of the metabolites was made by mass chromatography using deuterium-labeled internal standards. Approximately 4% of the dose was excreted as unchanged I within 32 hr after oral administration. The major metabolites identified in the neutral and basic fractions of the urine were N-acetylafloqualone (II, 0.3% of the dose), N-acetyl-2'-hydroxymethylafloqualone (III, 5.5%), N-glycolylafloqualone (IV, 0.9%), and N-glycolyl-2'-hydroxy-methylafloqualone (V, 1.3%). I and IV were also excreted in conjugated form as N-glucuronide (VI, 8.0%) and O-glucuronide and/or sulfate (VII, 0.4%), respectively. Other phenolic and sulfur-containing metabolites of I, which have previously been identified in the urine of rats, dogs, or monkeys, were not detected in the human urine. Thus, the main routes of metabolism of I in man consist of N-acetylation followed by hydroxylation at the 2'-methyl and acetylmethyl carbons, and glucuronidation of the aromatic amino group. This pattern of metabolism of I in man was in part similar to that observed in rats and monkeys, but drastically different from that in dogs.     

Metabolism and disposition of 14C-granisetron in rat,dog and man after intravenous and oral dosing

1. The disposition and metabolic fate of ¹⁴C-granisetron, a novel 5-HT₃ antagonist, was studied in rat, dog, and male human volunteers after intravenous and oral administration.

2. Complete absorption occurred from the gastrointestinal tract following oral dosing, but bioavailability was reduced by first-pass metabolism in all three species.

3. There were no sex-specific differences observed in radiometabolite patterns in rat or dog and there was no appreciable change in disposition with dose between 0·25 and 5 mg/kg in rat and 0·25 and 10mg/kg in dog. Additionally, there were no large differences in disposition associated with route of administration in rat, dog and man.

4. In rat and dog, 35–41% of the dose was excreted in urine and 52–62% in faeces, via the bile. Metabolites were largely present as glucuronide and sulphate conjugates, together with numerous minor polar metabolites. In man, about 60% of dosed radioactivity was excreted in urine and 36% in faeces after both intravenous and oral dosing. Unchanged granisetron was only excreted in urine (5–25% of dose).

5. The major metabolites were isolated and identified by MS spectroscopy and nmr. In rat, the dominant routes of biotransformation after both intravenous and oral dosing were 5-hydroxylation and N1-demethylation, followed by the formation of conjugates which were the major metabolites in urine, bile and plasma. In dog and man the major metabolite was 7-hydroxy-granisetron, with lesser quantities of the 6,7-dihydrodiol and/or their conjugates.     

Biotransformation of linogliride,a hypoglycemic agent in laboratory animals and humans

Following oral administration of linogliride, a hypoglycemic agent, to rat (50 mg kg⁻¹), dog (30 mg kg⁻¹), and man (100 mg per subject), plasma, urine, and fecal extract sample pools were obtained. Nine metabolites plus unchanged linogliride were isolated and identified. The number of metabolites identified were: rat (5), dog (9), and man (1). In each species, more than 78% of the administered dose was recovered in the urine pools. Identified metabolites were estimated to account for >82% of the total amounts of drug-related sample in urine pools and >50% in plasma and fecal extract pools.Formation of linogliride metabolites in the three species can be described by four proposed pathways: pyrrolidine hydroxylation, aromatic hydroxylation, morpholine hydroxylation, and imino-bond cleavage. Comparison of the proposed metabolic pathways among species reveals a similarity between rat and dog. In these two species, pyrrolidine hydroxylation was quantitatively the most important pathway, with 5-hydroxylinogliride and dominant hypoglycemic active metabolite in all sample pools. Further oxidation of 5-hydroxylinogliride resulted in the formation of five minor metabolites. The other three pathways appeared to be quantitatively unimportant.Metabolism of linogliride in man occurred to a very limited extent. More than 90% of the total linogliride-related material in plasma was the unchanged drug. Greater than 76% of the administered dose was excreted unchanged in the urine. Only 5-hydroxylinogliride was identified in minor amounts in human samples.     

The metabolic disposition of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-cyanopyridine in rats, dogs, and humans

Studies of the metabolic disposition of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-[14C]cyanopyridine (I) have been performed in humans, dogs, and spontaneously hypertensive rats. After an iv injection of I (5 mg/kg), a substantial fraction of the radioactivity was excreted in the feces of rats (32%) and dogs (31%). After oral administration of I (5 mg/kg) the urinary recoveries of radioactivity for rat and dog were 19% and 53%, respectively, and represented a minimum value for absorption because of biliary excretion of radioactivity. In man, bililary excretion of I appeared to be of minor significance because four male subjects, after receiving 6 mg of I p.o., excreted 76% and 9% of the dose of radioactivity in the urine and feces, respectively. Unchanged I represented 58% of the radioactivity excreted in human urine. The half-life for renal elimination of I was determined to be 4.0 +/- 0.9 /hr. In contrast, unchanged I represented 7% and 1% of excreted radioactivity in rat and dog urine, respectively. A metabolite of I common to man, dog, and rat was identified as 5-hydroxy-I, which represented approximately 5% of the excreted radioactivity in all species. Minor metabolites of I in which the pyridine nucleus had undergone additional hydroxylation were present in dog urine along with an oxyacetic acid metabolite, also bearing a hydroxylated pyridine nucleus.     

Metabolism and disposition of sulfinalol in laboratory animals

Peak levels of radioactivity in blood occurred 1.0 hr after oral administration of 3H-sulfinalol hydrochloride to rats, dogs, and monkeys. The plasma decay curve for intact sulfinalol in the dog was biphasic, with apparent first-order half-lives of 0.55 and 6.2 hr. Rats excreted 42.5% of the dose in the urine and 31.8% in the feces after 24 hr. Urinary and fecal recovery were 53.8% and 41.2%, respectively, after 10 days for dogs and 57.8% and 38.0%, respectively, after 9 days for monkeys. Free sulfinalol (11.8% of the dose) was the major component in dog feces with lesser amounts of the sulfide and sulfone metabolites, also in the unconjugated form. All metabolites in dog urine were conjugated with glucuronic acid, with sulfinalol (28.5%) and desmethylsulfinalol (8.5%) representing the major constituents, whereas the sulfone and sulfide metabolites were minor ones. Monkey feces contained primarily unconjugated forms of the desmethyl sulfide metabolite (17.0%) and sulfinalol (7.5%); lesser amounts of desmethylsulfinalol and the sulfone metabolite were present. Desmethylsulfinalol (8.7%) and its sulfate (7.0%) and glucuronide (4.0%) conjugates were the major urinary metabolites in the monkey; sulfinalol (1.4%), its glucuronide conjugate (5.1%), the desmethyl sulfide metabolite (and its sulfate conjugate), and the sulfone metabolite were also present.     

Metabolic disposition of enciprazine, a non-benzodiazepine anxiolytic drug, in rat, dog and man.

1. The excretion and metabolism of enciprazine, an anxiolytic drug, was examined in rat, dog and man. 2. In rats and dogs that received 14C-enciprazine dihydrochloride orally and by i.v. injection, the drug was well absorbed. Radioactivity was excreted predominantly in the faeces of rats, equally in urine and faeces of dogs, and to a major extent in human urine. 3. Metabolic profiles, which were evaluated in urine and in rat bile, were similar following oral and i.v. dosing to rats and dogs. 4. Unchanged drug was not detected in rat, dog or human excreta. Glucuronide conjugates of 4-hydroxyenciprazine, m-desmethylenciprazine, p-desmethylenciprazine and enciprazine were detected in the excreta of all three species. A glycol metabolite was present only in rat bile and human urine. A metabolite desmethylated in the phenyl ring of the phenylpiperazine moiety also appeared to be present only in human urine. 5. Structural confirmation of the major metabolites in human urine and rat bile was accomplished by h.p.l.c.-mass spectrometry.     

The Metabolism of Ibuprofen

Abstract

1. After oral administration ibuprofen appeared mainly in unchanged form in the plasma of rats, dogs, baboons and men. It disappeared more slowly from the plasma of dogs than from that of other species. On repeated dosing it accumulated most in dog plasma.

2. Two metabolites, 2-[4-(2-hydroxy-2-methylpropyl)phenyl]propionic acid (metabolite A) and 2-[4-(2-carboxypropyl)phenyl]propionic acid (metabolite B), were found in rat, baboon and human plasma, but not in dog plasma. Both metabolites were found in the urines of all four species, but there were marked differences in proportions and extent of conjugation.

3. Rats excreted in bile about 28% of a single intravenous dose of [¹⁴C]ibu-profen in 3 hours and a dog excreted 25% in the same period. Biliary cannulation did not influence plasma radioactivity, suggesting that little enterohepatic circulation occurred.

4. At clinically significant concentrations ibuprofen was strongly bound to plasma protein in vitro, 95% being bound in baboon, 96% in rat, and 99% in dog and human plasma.

5. After administration of either (+) or (-)-ibuprofen to man, urinary metabolites A and B were dextrorotatory.

6. In the rat ibuprofen induced neither its own metabolism nor that of sodium pentobarbitone, but sodium pentobarbitone induced the metabolism of ibuprofen.