The metabolism of chlorpromazine N-oxide in the rat

1. The metabolism of chlorpromazine N-oxide was studied in female rats after a 20 mg/kg single oral dose. 2. Metabolites identified in both urine and faeces were chlorpromazine, 7-hydroxychlorpromazine, chlorpromazine sulphoxide, N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide. 3. Metabolites were separated by h.p.l.c. or g.l.c. prior to mass spectrometric analysis. The structures of the metabolites were confirmed by direct comparison of their mass spectra and chromatographic behaviours with those of authentic compounds. 4. Chlorpromazine N-oxide and any metabolite which retained the intact N-oxide function, such as chlorpromazine, N,S-dioxide, could not be identified in any of the extracts. 5. When 3H-chlorpromazine N-oxide was administered under the same conditions; approximately twice as much radioactivity was excreted in the faeces (52.1 +/- 9.7%) as in the urine (26.9 +/- 7.2%).     

The metabolism of 14C-labelled trimethylamine and its N-oxide in man

Abstract

1. The metabolism and elimination of ¹⁴C-labelled trimethylamine and its N-oxide (100?mg orally) were studied in three male volunteers.

2. For both compounds the urine was the major route of elimination, with 95% of the administered ¹⁴C being voided in the first 24?h. No radioactivity was found in expired air.

3. The majority (> 95%) of the urinary ¹⁴C from both compounds was excreted as trimethylamine N-oxide.     

The metabolism of 14C-labelled trimethylamine and its N-oxide in man

The metabolism and elimination of 14C-labelled trimethylamine and its N-oxide (100 mg orally) were studied in three male volunteers. For both compounds the urine was the major route of elimination, with 95% of the administered 14C being voided in the first 24 h. No radioactivity was found in expired air. The majority (greater than 95%) of the urinary 14C from both compounds was excreted as trimethylamine N-oxide.     

The metabolites of chlorpromazine N-oxide in rat bile

1. The metabolism of chlorpromazine N-oxide was studied in female rats after a 20?mg/kg single i.p. dose.

2. Metabolites identified in urine and faeces were chlorpromazine, 7-hydroxy-chlorpromazine, chlorpromazine sulphoxide, N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide. As these same five metabolites were previously shown to be present after oral administration this indicates that reduction of chlorpromazine N-oxide occurs not only in the gastrointestinal tract but also at other sites.

3. The metabolism of chlorpromazine N-oxide was studied following its administration by either i.p., i.v. or oral routes to female rats in which the bile duct was cannulated.

4. There were no qualitative differences between the three routes of administration with respect to the metabolites identified. With the exception of the absence of N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide, all metabolites previously identified in urine and faeces were also present in bile.

5. Additionally there were three compounds present in rat bile which were not identified in urine or faeces. These were chlorpromazine N-oxide, chlorpromazine N, S-dioxide and 7-hydroxychlorpromazine O-glucuronide. This is the first unequivocal evidence for the identification of intact 7-hydroxychlorpromazine O-glucuronide in any species.

6. The inability to detect chlorpromazine N-oxide and chlorpromazine N, S-dioxide in the faeces of rats is likely to be due to the reduction of the N-oxide group on the passage of these biliary metabolites down the intestinal tract.     

The metabolism of carfecillin in rat,dog and man

1. The absorption of the phenol moiety of [phenol-¹⁴C]carfecillin following oral administration to rat, dog and man was extensive, since 95%, 73% and 99% of the administered radioactivity respectively was recovered in the urine. In contrast, less than half of the carbenicillin moiety of carfecillin was absorbed after oral administration, as judged by excretion studies using [carbenicillin-¹⁴C]carfecillin in intact and bile-duct cannulated animals.

2. The patterns of radiometabolites in the urines of rat, dog and man following single oral administration of [phenol-¹⁴C]carfecillin were determined by chromatography and radioassay. In two men, the majority of a dose was excreted as phenylsulphate (71%) and phenylglucuronide (16%) with the sulphate and glucuronic acid conjugates of quinol representing small amounts of the urinary radioactivity. Similar metabolic patterns were observed in the rat and dog following oral administration of either [¹⁴C]phenol or [phenol-¹⁴C]carfecillin, although some saturation of sulphate conjugation was apparent at the dose levels employed.     

The metabolism of talampicillin in rat, dog and man

1. After administration of [phthalidyl-14C] 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 radiometabolites was very similar in extracts of the urines of radiometabolites 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.     

The metabolism of carfecillin in rat, dog and man

1. The absorption of the phenol moiety of [phenol-14C]carfecillin following oral administration to rat, dog and man was extensive, since 95%, 73% and 99% of the administered radioactivity respectively was recovered in the urine. In contrast, less than half of the carbenicillin moiety of carfecillin was absorbed after oral administration, as judged by excretion studies using [carbenicillin-14C]carfecillin in intact and bile-duct cannulated animals. 2. The patterns of radiometabolites in the urines of rat, dog and man following single oral administration of [phenol-14C]carfecillin were determined by chromatography and radioassay. In two men, the majority of a dose was excreted as phenylsulphate (71%) and phenylglucuronide (16%) with the sulphate and glucuronic acid conjugates of quinol representing small amounts of the urinary radioactivity. Similar metabolic patterns were observed in the rat and dog following oral administration of either [14C]phenol or [phenol-14C]carfecillin, although some saturation of sulphate conjugation was apparent at the dose levels employed.     

The metabolites of chlorpromazine N-oxide in rat bile.

1. The metabolism of chlorpromazine N-oxide was studied in female rats after a 20 mg/kg single i.p. dose. 2. Metabolites identified in urine and faeces were chlorpromazine, 7-hydroxychlorpromazine, chlorpromazine sulphoxide, N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide. As these same five metabolites were previously shown to be present after oral administration this indicates that reduction of chlorpromazine N-oxide occurs not only in the gastrointestinal tract but also at other sites. 3. The metabolism of chlorpromazine N-oxide was studied following its administration by either i.p., i.v. or oral routes to female rats in which the bile duct was cannulated. 4. There were no qualitative differences between the three routes of administration with respect to the metabolites identified. With the exception of the absence of N-desmethylchlorpromazine and N-desmethylchlorpromazine sulphoxide, all metabolites previously identified in urine and faeces were also present in bile. 5. Additionally there were three compounds present in rat bile which were not identified in urine or faeces. These were chlorpromazine N-oxide, chlorpromazine N,S-dioxide and 7-hydroxychlorpromazine O-glucuronide. This is the first unequivocal evidence for the identification of intact 7-hydroxychlorpromazine O-glucuronide in any species. 6. The inability to detect chlorpromazine N-oxide and chlorpromazine N,S-dioxide in the faeces of rats is likely to be due to the reduction of the N-oxide group on the passage of these biliary metabolites down the intestinal tract.     

Effects of chlorpromazine on the metabolism of catecholamines in dog brain

1. The effect of chlorpromazine (CPZ) on the metabolism of dopamine and 5-hydroxytryptamine in dog brain was investigated by following the concentrations of the acid metabolites of these amines, homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid, in the ventricular cerebrospinal fluid (C.S.F.) of dogs over a period of 5 hr after intravenous administration of CPZ (2.5, 5, 10 and 15 mg/kg), using the technique of serial sampling of lateral ventricular C.S.F. "Low" doses (2.5-10 mg/kg) produced a rise in the concentration of homovanillic acid and smaller increases in the concentrations of 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid. "High" doses (10-15 mg/kg) had a lesser effect on the concentration of homovanillic acid and had no effect on, or decreased, the concentrations of 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid. The concentration of 3,4-dihydroxyphenylacetic acid was maximal in the ventricular C.S.F. 2 hr after CPZ 5 mg/kg and was unaltered from the control level 2 hr after 15 mg/kg.2. The effects on the metabolism of brain amines of CPZ (5 mg/kg), doses which the serial sampling of C.S.F. experiments had indicated as producing maximal and minimal effects on dopamine metabolism in brain tissue, were studied by estimating the concentrations of adrenaline, noradrenaline, dopamine, metanephrine, methoxydopamine, homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid in the hypothalamus, midbrain, thalamus, hindbrain, cortex, globus pallidus and caudate nucleus of control dogs and of dogs treated with CPZ intravenously 2 hr before killing. The concentrations of homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid were estimated in samples of ventricular C.S.F. withdrawn from these dogs 2 hr after the injection of CPZ (i.e., immediately before death).3. The following changes in concentrations were observed. Dopamine: CPZ 5 mg/kg produced no change in the concentration in the caudate nucleus, globus pallidus and midbrain and increased the concentration in the thalamus; CPZ 15 mg/kg appeared to cause a reduction in the concentration of this amine in the caudate nucleus and globus pallidus. Homovanillic acid and 3,4-dihydroxyphenylacetic acid: CPZ 5 mg/kg increased the concentrations of both acids in the caudate nucleus and had no effect on the concentrations of the acids in the globus pallidus, hypothalamus and thalamus; CPZ 15 mg/kg produced no change in the concentrations of the acids in any area of the brain. Methoxydopamine: CPZ 5 mg/kg and 15 mg/kg reduced the concentration in the caudate nucleus. Noradrenaline: The concentrations in the hypothalamus, midbrain, thalamus and hindbrain were slightly increased by CPZ 5 mg/kg and 15 mg/kg. Only in the thalamus was a statistically significant increase in noradrenaline observed.4. It was concluded that the actions of chlorpromazine on catecholamine synthesis and metabolism in the brain of the dog are dose dependent. A dose of CPZ 5 mg/kg was postulated to have the following actions: (i) to increase dopamine synthesis; (ii) to activate mitochondrial monoamine oxidase. A dose of CPZ 15 mg/kg was postulated to act as follows: (i) to decrease dopamine synthesis; or (ii) to release dopamine from its storage sites.5. The ratios of the concentrations of homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindolylacetic acid in the caudate nucleus to the concentrations of these acids in the ventricular C.S.F. were the same in the control dogs as in the dogs treated with CPZ (5 mg/kg and 15 mg/kg). It was concluded that the levels of the acid metabolites of dopamine in lateral ventricular C.S.F. reflect the levels of these acids in the caudate nucleus.     

The metabolism of nafimidone hydrochloride in the dog, primates and man

1. The biotransformation of nafimidone, an imidazole-substituted anticonvulsant, has been studied by characterization of urinary metabolites in dogs, cynomolgus monkeys, baboons and man. 2. The biotransformation of nafimidone in these laboratory animals and man is initially very similar, in each case proceeding by reduction to the aliphatic alcohol metabolite, nafimidone alcohol or 1-[2-hydroxy-2-(2-naphthyl)ethyl]imidazole. 3. Further transformation of this metabolite involves oxidation in the naphthyl and imidazole functions, and/or conjugation. 4. The dog differs from the higher primates in that no metabolic modification of the naphthyl group takes place, the major metabolite in the dog being the O-beta-glucuronide of nafimidone alcohol. 5. In higher primates and man two isomers involving dihydroxylation in the naphthyl ring--1-[2-hydroxy-2-(5,6- or 7,8-dihydroxydihydro-2-naphthyl)ethyl]imidazole--were tentatively identified. These species alone showed evidence of an imidazole linked N-glucuronide of nafimidone alcohol. 6. The possible occurrence of stereoselective metabolism by the introduction of a chiral centre at C-9 in nafimidone alcohol was indicated in human urine by the presence of both epimers of the O-beta-glucuronide of nafimidone alcohol in a 2:1 ratio.     

Kinetics and metabolism of 2,2-diethylallylacetamide in dog and man

Summary In dogs, slow intravenous injection of 100 mg of diethylallylacetamide (DA) resulted in maximal blood levels of 10–14 g/ml, and a rapid phase of elimination during 90 min with a half life of 45 min, followed by a slower elimination rate with a half life of 80–90 min.After oral application of 30 mg DA/kg to female beagle dogs, maximal blood levels of 14 g/ml were observed after 90–120 min. The blood concentrations declined with a mean half life of 5 h.In human volunteers, oral doses of 250 mg DA, or rectal application of 300 mg DA produced highest mean blood levels of 4.8 g/ml (orally), and 5.4 g/ml (rectally) after 180 min. The mean blood half life was 7.2 h (orally), and 9.2 h (rectal application). Undesirable effects such as nausea, vomiting, and disorientation began to appear at blood levels above 5 g/ml.In the urine of dogs and human volunteers, only 2–3% of unchanged DA was recovered, and less than 1% of 2,2-diethyl-4,5-dihydroxypentanoic acid--lactone (DA-lactone) was identified. Acid hydrolysis of the human urine liberated a total of 14–16% of DA-lactone. This percentage was not increased by splitting the urinary conjugates with glucuronidase and glusulase. Small amounts of 2,2-diethylallylacetic acid, 2,2-diethyl-4-one-pentanoic acid, and 2,2-diethyl-4,5-dihydroxypentanamide were detected.The new metabolites described were synthetized and fully characterized.Abbreviations used in the text AIA allylisopropylacetamide - DA 2,2-diethylallylacetamide (2,2-diethyl-4-penteneamide) - DA-acid 2,2-diethylallylacetic acid (2,2-diethyl-4-pentenoic acid) - DA-lactone 2,2-diethyl-4,5-dihydroxypentanoic acid--lactone - DA-glycol 2,2-diethyl-4,5-dihydroxypentanamide The results were presented at the 17th Spring Meeting of the German Pharmacological Society (Brinkschulte-Freitas and Uehleke, 1976). Parts of the results are included in the dissertation of Brinkschulte (1975)     

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.     

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 pharmacokinetics and metabolism of Kö 592 in man,dog and rat

Summary Plasma concentration, renal and faecal excretion, absorption and metabolism of the tritiated beta-adrenergic blocker Kö 592 were studied in man, dog and rat. The substance was absorbed to an extent of 90–100% in all species (rat within 30 min, dog within 80 min, man within 120 min). The half-life of radio-activity in the plasma was 3 h in man and dog, in the rat blood 11 h. Excretion is almost complete within the first 12 h in man and dog. While 10–20% of the substance appears in the faeces in rats, elimination in the dog and man is almost exclusively renal. Kö 592 is completely metabolized. The metabolites were isolated from urine and identified by mass spectrometry. With individual variations, 31% of the metabolites of man and dog were present as methylphenoxy lactic acid, 20% as p-hydroxy-Kö 592 and 50% as conjugates. Man conjugates only with glucuronic acid, the dog conjugates 50% with sulphate and 50% with glucuronide.     

Pharmacokinetics and metabolism of gabapentin in rat, dog and man

This paper describes the pharmacokinetic studies of 1-(aminomethyl)-cyclohexane acetic acid (gabapentin, G? 3450, CI-945) conducted with the 14C-labelled substance following intravenous and intragastric administration to rats and dogs and oral administration to humans. Gabapentin is well absorbed in rats, dogs and in humans, with maximum blood levels, reached within 1-3 h after peroral administration. Following i.v. administration to rats, similar blood and brain levels of gabapentin are observed after a short distribution phase, whereby concentrations in cerebrum and cerebellum are comparable. The highest concentrations are found in the pancreas and kidneys and the lowest values in adipose tissue. No binding of gabapentin to human plasma proteins or human serum albumin is observed. The distribution coefficient (octanol/buffer pH 7.4) is 7.5 X 10(-2). In man, no biotransformation of gabapentin is observed. In rats, biotransformation is only minor. In dogs, however, a remarkable formation of N-methyl-gabapentin is found. Elimination half-lives range between 2-3 h in rats, 3-4 h in dogs, and 5-6 h in man. Gabapentin is nearly exclusively eliminated via the kidneys. Renal elimination was up to 99.8% in rats and approx. 80% in man following oral administration. The blood level-time course after i.v. administration to rats can well be described by a three-compartment open model. Experiments in rats and dogs demonstrate that pharmacokinetics are not sex-dependent and are not changed after multiple dosage. Pharmacokinetics are shown to be linear in the range tested of 4 to 500 mg/kg i.v. in rats.     

Comparative metabolism of cannabidiol in dog, rat and man.

Urinary metabolites of cannabidiol (CBD) were extracted from human, dog and rat urine, concentrated by chromatography on Sephadex LH-20, and identified by GC/MS. Over 50 metabolites were identified with considerable species variation. CBD was excreted in substantial concentration from human urine, both in the free state and as its glucuronide. In dog, unusual glucoside conjugates of three metabolites (4'- and 5'-hydroxy and 6-oxo-CBD), not excreted in the unconjugated state, were found as the major metabolites at early times after drug administration. Other metabolites in all three species were mainly acids. Side-chain hydroxylated derivatives of CBD-7-oic acid were particularly abundant in human urine but much less so in dog. In the latter species the major oxidized metabolites were the products of beta-oxidation with further hydroxylation at C-6. A related, but undefined pathway, resulted in loss of three carbon atoms from the side-chain of CBD in man with the production of 2'-hydroxy-tris,nor-CBD-7-oic acid. Previous experiments indicate that 3'-hydroxy-metabolites are the precursors of compounds having this side-chain. Metabolism by the epoxide-diol pathway, resulting in dihydro-diol formation from the delta-8-double bond, gave metabolites in both dog and human urine. It was concluded that CBD could be used as a probe of the mechanism of several types of biotransformation, particularly those related to carboxylic acid metabolism, as intermediates of the type not usually seen with endogenous compounds were excreted in substantial concentration.     

Chlorpromazine metabolism. IX. Pharmacokinetics of chlorpromazine following oral administration in man

A single oral dose (120 mg/m²) of Chlorpromazine hydrochloride was administered to four healthy subjects and the blood levels of Chlorpromazine were determined with time. Appropriate equations describing the two-compartment open model with zero-order absorption and the two-compartment model with first-order absorption, both with a lag time, were fitted to the observed data using weighted nonlinear least-squares regression analysis. Fitting the two-compartment model with zero-order absorption and a lag time to the observed data resulted in a significant reduction of the weighted sum of squared deviations, i.e., better correlation between the observed and calculated data, and a closer random scatter of the observed concentration data around the calculated curve with no apparent systematic deviations from the curve. These results suggest that Chlorpromazine absorption is zero order. Chlorpromazine began to appear in the systemic circulation after a mean lag time of 0.4 hr and continued to be absorbed for approximately 2.9 hr. The mean half-lives of the distribution and elimination phases were 1.63 and 17.7 hr, respectively.This work was supported in part by National Institute of Mental Health Grant No. MH 21408-02, NIH.Presented by L. Whitfield at the Twenty-third National Meeting of the APhA Academy of Pharmaceutical Sciences, November 13–17, 1977.