Excretion and Biotransformation of Carboxymethyl-cysteine in Rat,Dog, Monkey and Man

1. Following an oral dose of S-carboxymethyl[³⁵S]cysteine, monkey (rhesus and African green), rat, dog, and man excreted 77, 88, 95, and 100% respectively of the ³⁵S radioactivity in urine and 7·0, 2·5, 0·7, and 0·3% in faeces during a 3 to 4 day period.

2. The principal drug-related components excreted were unchanged carboxymethylcysteine, dicarboxymethyl sulphide and inorganic sulphate.

3. Rat, dog, and man excreted primarily dicarboxymethyl sulphide and unchanged carboxymethylcysteine and no inorganic sulphate (rat, 7%).

4. Monkey excreted largely inorganic sulphate, moderate amounts of dicarboxymethyl sulphide and a trace of unchanged drug.     

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.     

Disposition and metabolism of a novel diurea inhibitor of acyl CoA: cholesterol acyltransferase (YM17E) in the rat and dog

We have investigated the disposition and metabolism of YM17E after intravenous and oral administration in the rat and dog.

2. Unavailability of YM17E was 5–9% at oral doses of 3–30 mg/kg in rat, and 9 and 13% at oral doses of 10 and 30mg/kg in dog.

3. Five N-demethylated metabolites, which have significant pharmacological activity, were found in rat and dog plasma after oral administration. Plasma concentrations of each of these metabolites were comparable with (hat of unchanged drug.

4. When ¹⁴C-YM17E was administered to rat, AUC of unchanged drug was 7% of that of radioactivity. However, AUC of the combined concentration of unchanged drug and five active metabolites was about 50% of that of radioactivity, indicating that the pharmacological activity of the agent was maintained in spite of its biotransformation.

5. After oral administration of ¹⁴C-YM17E at a dose of 10 mg/kg to rat, radioactivity was distributed widely to almost all tissues except the brain. The concentration of radioactivity in the liver, one of the target organs, was 65 times higher than that in plasma at 1 h after administration.

6. A significant amount of radioactivity in the liver was located in the microsomal subfraction, which contains much acyl CoA: cholesterol acyl transferase activity. More than 50% of this microsomal radioactivity was derived from unchanged YM17E and five active metabolites.

7. From excretion data in the bile duct-cannulated rat, the absorption ratio of YM17E from the gastrointestinal tract in this species was estimated to be at least 40%, suggesting that the low bioavailability of the drug is due to extensive first-pass metabolism.

8. Some 95% of the administered radioactivity was excreted in the faeces of rat following iv or po doses of ¹⁴C-YM17E.     

The Metabolism of Talampicillin in Rat,Dog and Man

1. After administration of [phthalidyl-¹⁴]talampicillin (Talpen® to rat. dog and man, radioactivity was excreted mainly in the urine (90%, 86% and 98% in rat, dog and man respectively).

2. After administration of [ampicillin-¹⁴C]talampicillin, radioactivity was excreted in the urine of rats and dogs to a lesser extent (35% in both species) and only a small proportion of the dose was excreted in the bile (6% in rats, less than 0·1% in dogs).

3. The pattern of radiometaboletes was very similar in extracts of the urines of rat, dog and man dosed orally with [phthalidyl-14C]talampicillin. The major metabolite was 2-hydroxymethylbenzoic acid.

4. Unchanged talampicillin was present in the hepatic portal vein blood of dog and thus reached the liver, whereas in rat, no parent compound could be detected in portal vein blood. This result may help to explain differences in toxicity of the compound in rat and dog.

5. Studies in vitro showed that the intestinal wall is an important site of hydrolysis of talampicillin in rat and dog.     

Biotransformation of sultopride in man and several animal species

1. The biotransformation of sultopride has been investigated in rat, rabbit, dog and man.

2. In man sultopride was metabolically stable, and about 90% of an oral dose was excreted in urine unchanged and 4% as oxo-sultopride.

3. Rat, rabbit and dog metabolized sultopride more extensively and excreted less than 40% of an oral dose of ¹⁴C-sultopride in urine.

4. Four similar metabolites were excreted by the three animal species but the relative portions differed. The major radioactive component in rat urine was O-desmethyl sultopride, whereas oxo-sultopride and O-desmethyl sultopride were the major urinary metabolites in rabbit. Dog formed N-desethyl sultopride and oxo-sultopride as major urinary metabolites.

5. The male rat excreted smaller amounts of unchanged sultopride in urine than did the female rat.

6. The unchanged sultopride excreted in rat urine was increased slightly by repeated administration.     

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.     

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.     

Absorption,distribution and excretion of lacidipine,a dihydropyridine calcium antagonist,in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog).

2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism.

3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug.

4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species.

5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses.

6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration.

7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.     

The Metabolism of Terbutaline in Dog and Rat

Abstract

1. The metabolic fate of [³H]terbutaline has been studied in dog after oral, intravenous and subcutaneous administration and in rat after oral and intravenous administration. In 3–4 days the dog excreted 75% of the dose in the urine after oral administration and more than 90% after intravenous or subcutaneous administration; the remainder was in the faeces. The rat in 24 h excreted about 13% in the urine and 61% in the faeces after oral administration and 48% in the urine and 35% in the faeces after intravenous administration.

2. After oral administration of [³H]terbutaline, the time course of radioactivity concentration was the same in lung, heart and serum; low levels of unchanged drug were found in all tissues. After intravenous administration, the concentration of unchanged drug was higher in lung and heart than in serum.

3. In dog, 1·7% of an intravenous dose was excreted into bile in 6 h. In rat, about 37% of the dose was recovered in the bile during 12 h.

4. Enzymic hydrolysis of urine showed that terbutaline is metabolized by conjugation, forming a glucuronide in rat but probably a sulphate in dog.     

Kinetics and disposition of picumeterol in animals

1. The pharmacokinetics and disposition of picumeterol, a novel β₂ receptor agonist agent, have been studied in the rat and dog following administration by inhalation, intravenous and oral routes at various dose levels.

2. Picumeterol was found to be transferred across the lung of the rat and dog following inhalation dosage. After i.v. dosage picumeterol was eliminated from plasma with a half-life of about 1?h in the rat and about 2?h in the dog. Plasma clearance in the rat was about twice liver blood flow and the plasma levels of picumeterol were low after oral administration.

3. Following instillation of ¹⁴C-picumeterol to the trachea of isolated respiring rat lung preparations radioactivity was transferred from the airways to perfusion media as unchanged drug within 2?min. After 2?h perfusion, no metabolites were detected in the recirculation perfusate or lung.

4. Picumeterol was extensively metabolized in vivo in the rat (about 95%) and dog (about 90%) and in vitro in microsomal preparations of rat, dog and human liver. O-dealkylation and β-oxidation are important as routes of metabolism.

5. Radioactivity was largely excreted in the urine of the rat and dog (> 50% of dose), as metabolites, following i.v. administration. There was some excretion of radioactivity in dog bile. Extensive first-pass metabolism was found after oral administration in the rat.     

Identification of an N-Oxide as the Major Metabolite of the Analgesic O-(Diethylaminoethyl)-4-Chlorobenz-aldoxime Hydrochloride in Dogs

1. After oral administration to dogs of the analgesic O-(diethylaminoethyl)-4-chloro[7-¹⁴C]benzaldoxime hydrochloride together with piperazine hydro-chloride (2:1, w/w), at a dose of 4.5?mg/kg, the radioactivity was well absorbed and rapidly excreted. During 5 days, 81% of the dose (ca. 50% in 12?h) was excreted in urine and 10% in faeces.

2. Rates and routes of excretion of radioactivity were not altered in animals pre-treated with the drug for fourteen days.

3. Peak mean plasma concentrations of radioactivity (5.5 μg equiv./ml) occurred at 90 min after an oral dose and were higher than those at 2 min following an equivalent intravenous (3.4 μg equiv. /ml) or rectal (4.0 μg equiv. /ml) dose which gave a max. at 45?min.

4. The drug was rapidly and extensively metabolized and no unchanged drug was detected in the plasma or urine. The major urinary metabolite was the N-oxide of the parent compound accounting for 34% and 23% dose excreted in the urine of males and females respectively during 12?h after administration.     

Absorption,distribution, metabolism and excretion of a new, 14C-labelled oxazolidinone MAO-A inhibitor in rat and dog

1. After oral administration of ¹⁴C-labelled (5R)-3-\[2-((1S)-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidinone (E2011) at a dose of 1?mg/kg, the blood level of radioactivity reached a maximum concentration (C_max) of 0.545 μg eq./ml after 0.25?h in the rat and of 0.900 μg eq./ml after 0.5?h in the dog. In dog plasma, C_max for radioactivity and unchanged E2011 were 0.862 μg eq./ml and 0.650 μg/ml respectively with corresponding T_max (time at C_max) of 0.75 and 0.25?h. The unchanged drug in dog plasma was below the detection limit (5 ng/ml plasma) after 24?h. 2. The tissue levels of radioactivity were measured at 0.25 (T_max), 6, 24, and 168?h after max administration to the rat and at 0.5 (T_max), 24, and 168?h in the dog. The radioactivity was max distributed in all tissues examined at T_max in the rat and dog. The radioactivity levels of the cerebral cortex in the rat and dog were 26 and 36% of the plasma level at T_max. The radioactivity in tissues decreased at almost the same rate as that in plasma. Plasma protein binding of the unchanged drug in the rat in vitro were about 70% in the range of 0.1-10 μg/ml, and those in the dog were about 45% in the same concentration range. 3. Cumulative excretion of radioactivity in the rat was 74.5% in urine and 22.5% in faeces after 7 days. In the dog, 55.5 and 36.5% of the radioactivity administered were excreted in urine and faeces respectively after 7 days. The biliary excretion of radioactivity in the cannulated rat was 23.0% within 48?h. 4. In tlc analysis of plasma and tissues of the rat and dog, the radioactivity for the unchanged drug was much higher than metabolites. In tlc analysis of urine, the same metabolites were detected in the rat and dog, and the radioactivity of a metabolite, IM1, was the highest in the both animals. Eight metabolites were detected in the plasma, tissues and excreta of the rat, and four metabolites in the dog. 5. In conclusion, the absorption, distribution, metabolism and excretion of ¹⁴C-labelled E2011 in the rat and dog have been established, and only minor differences were observed between these species.     

Metabolites of 2-(3-Trifluoromethylphenyl)Tetrahydro-1,4-Oxazine (Cerm 1841) in Rats and Dogs

1. In rats and dogs dosed with ¹⁴C-labelled 2-(3-trifluoromethylphenyl)tetrahydro-1,4-oxazine hydrochloride, the ¹⁴C was excreted mainly in the urine. The ¹⁴C eliminated in the faeces of dog was significantly higher than for rat.

2. Conjugated metabolites, mostly glucuronides, accounted for the greater part of the urinary radioactivity in both species.

3. Biotransformation products were predominantly acids in both species, followed by significant amounts of basic metabolites, with very little neutral substances.

4. The major urinary metabolite in rats was 3-trifluoromethylbenzoic acid and 3-trifluoromethylhippuric acid. In the dog it was 3-trifluoromethylmandelic acid in addition to the benzoic acid and its conjugate. The basic products identified in the urine of both species were unchanged drug and 1-amino-2-hydroxy-2-(3-trifluoromethylphenyl)ethane, with the first predominating.     

The physiological disposition of the anti-tussive agent, 1,2,3,4a,9b-hexahydro-8,9b-dimethyl-4-[3-(4-methylpiperazin-1-yl)propionamido]dibenzofuran-3-one dihydrochloride Azipranone, in man, rat, dog and baboon.

1. The absorption, tissue distrigution, elimination and biotransformation of the anti-tussive agent Azipranone labelled with 14C have been investigated after oral dosing to rat, dog, baboon and man and parenteral administration to rat and baboon. 2. Levels of radioactivity in plasma were maximal within 20 min of dosing in the rat and after 1-2 h in the remaining species. The concn. declined thereafter with a half-life estimated at 1, 3-4 and 18-24 h for rat, dog, and baboon and man respectively. 3. Three human volunteers excreted 53, 62 and 70% of the radioactivity in the urine in 96 h while the remaining species excreted 50-70% of the dose in the faeces in the same period. 4. Radioactivity was rapidly and extensively eliminated in the bile of both rat and baboon after administration of [14C]Azipranone. 5. The 24 h urine samples from all species contained ten major and a similar number of minor radioactive components. 6. In hepatic microsomal preparations, biotransformations of Azipranone are catalysed by enzymes requiring both NADPH2 and cytochrome-P450.     

Absorption,metabolism and excretion of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat and dog

1. The oral no overall adverse effect level (NOAEL) for chronic toxicity of 4-chloro-2-methylphenoxyacetic acid (MCPA) in rat is ~1.3?mg kg^-1 and in dog is 0.2 mgkg^-1. In an attempt to explain the difference in toxicology between these species, rats and dogs were orally dosed with (¹⁴C)-MCPA at 5 or 100?mg kg^-1 and plasma toxicokinetics, rates and routes of excretion and biotransformation were investigated. 2. Elimination of radioactivity in rat plasma was biphasic and in dog was monophasic. Rat eliminated radioactivity from plasma significantly faster than dog (approximate values based on total radioactivity: 5 mgkg^-1 rat: t_½dist 3.5 h, t_½elim 17.2-36.2 h, AUC_(0-∞) 230 µg equiv h g^-1; 5 mgkg^-1 dog: t_½47 h, AUC_(0-∞) 2500 µg equiv h g^-1; 100mg kg^-1 rat: t_½dist 10 h, t_½elim 10.27-25.4 h, AUC_(0-∞) 5400 µg equiv h g^-1; 100?mg kg^-1 dog: t_½41 h, AUC_(0-∞) 20 500µg equiv h g^-1). 3. For both species, the principal route of excretion was in urine but renal elimination was notably more rapid and more extensive in rat. 4. In both rat and dog, excretion of radioactivity was mainly as MCPA and its hydroxylated metabolite hydroxymethylphenoxyacetic acid (HMCPA). In rat, both were mainly excreted as the free acids although a small proportion was conjugated. In dog, the proportion of HMCPA was increased and the majority of both species was excreted as glycine or taurine conjugates. 5. These data, along with previously published accounts, indicate that renal elimination of MCPA in dog is substantially slower than in rat resulting in disproportionate elevation of AUC (based on total radioactivity) in dog compared with rat.     

In vivo biotransformation of fenoctimine in rat,dog and man

1. The metabolism of fenoctimine (Fn) was studied in rat, dog and man following administration of ¹⁴C-Fn sulphate.

2. Seventeen Fn metabolites were isolated by hplc and tlc from rat bile, dog bile, dog urine, human urine, human faecal extracts, and human plasma and identified using nmr and MS.

3. The identified metabolites accounted for 75% of total radioactivity in rat bile, 80% in dog bile, and 40% in dog urine samples. In man, 90% of the urinary, 70% of the faecal, and > 50% of the plasma total radioactivity were identified.

4. Three major pathways for Fn metabolism were proposed. These pathways involved imino-bond cleavage, aromatic hydroxylation and oxidation of the aliphatic chain.

5. The imino-bond cleavage pathway was dominant in all species. However, the other two pathways differed in quantitative importance among the species studied.

6. The aromatic hydroxylation pathway appeared to be the most important means of biotransformation of Fn in dog since all but two of the metabolites were formed by this route.

7. The aliphatic oxidation pathway appeared to be important to the biotransformation of Fn in man and produced three major metabolites.     

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.     

The Disposition of the Antitumour Agent 3,5-Diamino-1,2,4-triazole (Guanazole) in Mice,Rats and Dogs

Abstract

1. The disposition of ¹⁴C-guanazole has been examined in the mouse, rat and dog.

2. Guanazole is rapidly excreted in the urine of mice and rats after parenteral administration with 90% of the dose found in mouse urine 2 to 3 h following parenteral administration. Excretion of guanazole by the anaesthetized dog is slower than that by the mouse or rat with 80% appearing in the urine within 6h.

3. No evidence was found for the metabolism of guanazole and apparently this antitumour agent is excreted unchanged in these three species.

4. The rapid excretion of guanazole offers an explanation for its greater antitumour activity when given frequently rather than on a once a day schedule.     

The Fate of Phenglutarimide Hydrochloride in the Rat and Man

Abstract

1. In the rat, [¹⁴C]phenglutarimide HCl was completely absorbed from the gastrointestinal tract and totally excreted in the urine within 24 h after dosing. The drug was not metabolized.

2. [¹⁴C]Phenglutarimide was widely distributed throughout the body of the rat but only very low levels of radioactivity were detected in the brain. In pregnant animals the drug traversed the placenta and radioactivity was detected in the foetus and amniotic fluid in concentrations higher than or similar to those in the maternal plasma.

3. On absorption from the gastrointestinal tract, the drug was rapidly excreted into the urine and consequently tissue levels were low.

4. In man, after oral administration of non-radioactive phenglutarimide, the drug was excreted completely in the urine as the unchanged compound within 24 h after dosing.

5. In mice, phenglutarimide inhibited the peripheral but not the central actions of oxotremorine, an observation in accord with the distribution pattern of the drug in the rat.

6. Phenglutarimide inhibited the response of the isolated guinea-pig bladder to coaxial stimulation. It is suggested that sufficiently high concentrations of phenglutarimide may be reached in the bladder in vivo to inhibit the bladder reflex in man.     

Absorption, distribution and excretion of lacidipine, a dihydropyridine calcium antagonist, in rat and dog

1. The absorption, distribution and excretion of lacidipine have been studied in rat and dog after i.v. (0.05 mg/kg for rat; 0.5 mg/kg for dog) and oral dosage (2.5 mg/kg for rat; 2.0 mg/kg for dog). 2. Lacidipine was rapidly and extensively absorbed after oral dosing, in both species. Oral bioavailability was up to 26% in rat and up to 32% in dog, due to extensive first-pass metabolism. 3. After oral administration, peak levels of radioactivity were reached at 4-8 h in rat and 1-2 h in dog. Unchanged lacidipine peaked at 1-2 h in both species. Plasma levels of radioactivity were higher in female rats than in males but there was no difference in levels of unchanged drug. 4. After i.v. dosing the terminal half-life of unchanged drug was 2.9 h in rat and 8.2 h in dog. The half-life of radioactivity in plasma was longer in both species. 5. After both routes of administration, radioactivity was rapidly distributed in rat tissues with the highest concentration in liver, fat and gastrointestinal tract. Only traces of radioactivity were detected in the CNS and in rat foetuses. 6. Extensive biliary elimination occurred, and most of the radioactivity (73-95%) was excreted in the faeces after i.v. or oral administration. 7. The compound was extensively metabolized, no significant amount of unchanged drug was excreted in bile or urine.