1. The fate of orally administered (14)C-labelled l-alpha-methyldopa has been examined in three normal men and in eight hypertensive patients who responded to the drug and three who did not. 2. The output of (14)C in the urine in 2 days and in the faeces in 4 days was not very different in any of the subjects. The normals excreted about 40% of the dose in the urine and 60% in the faeces, the responders 52% (range 35-60%) and 45% and the non-responders 42% and 41%. Most of the urinary (14)C radioactivity was eliminated in 24h after dosing. 3. The main metabolite in the urine was free and conjugated alpha-methyldopa (normal men, 23%; responders, 37%; non-responders, 25% of the dose). Free and conjugated 3-O-methyl-alpha-methyldopa was about 4% in all subjects, total amines (alpha-methyldopamine and 3-O-methyl-alpha-methyldopamine) about 6% and ketones (mainly 3,4-dihydroxyphenylacetone) about 3%. 4. The output of alpha-methyldopamine (2-4% of dose), 3-O-methyl-alpha-methyldopamine (0.3%) and 3,4-dihydroxyphenylacetone (3-5%) was similar in the one normal and two responders examined. 5. The faecal (14)C in all subjects was unchanged l-alpha-methyldopa. 6. In general, the amounts of the metabolites in the urine in normal men and in responding and non-responding patients were quantitatively similar, except in one non-responding patient who converted nearly two-thirds of the absorbed drug into amines and ketones. There appeared to be no correlation between metabolites in the urine and response or lack of response to the drug. 7. In two normal subjects 70-80% of d-alpha-methyldopa was excreted unchanged in the faeces. Of the absorbed compound most (9-14% of the dose) was excreted as the free and conjugated drug together with a small amount (1-2%) of 3-O-methyl-alpha-methyldopa. No amines and only traces of ketone were excreted.

Adult↗

PubMed1972

Metabolism of ( 14 C)methamphetamine in man, the guinea pig and the rat.

1. The metabolites of (+/-)-2-methylamino-1-phenyl[1-(14)C]propane ([(14)C]methamphetamine) in urine were examined in man, rat and guinea pig. 2. In two male human subjects receiving the drug orally (20mg per person) about 90% of the (14)C was excreted in the urine in 4 days. The urine of the first day was examined for metabolites, and the main metabolites were the unchanged drug (22% of the dose) and 4-hydroxymethamphetamine (15%). Minor metabolites were hippuric acid, norephedrine, 4-hydroxyamphetamine, 4-hydroxynorephedrine and an acid-labile precursor of benzyl methyl ketone. 3. In the rat some 82% of the dose of (14)C (45mg/kg) was excreted in the urine and 2-3% in the faeces in 3-4 days. In 2 days the main metabolites in the urine were 4-hydroxymethamphetamine (31% of dose), 4-hydroxynorephedrine (16%) and unchanged drug (11%). Minor metabolites were amphetamine, 4-hydroxyamphetamine and benzoic acid. 4. The guinea pig was injected intraperitoneally with the drug at two doses, 10 and 45mg/kg. In both cases nearly 90% of the (14)C was excreted, mainly in the urine after the lower dose, but in the urine (69%) and faeces (18%) after the higher dose. The main metabolites in the guinea pig were benzoic acid and its conjugates. Minor metabolites were unchanged drug, amphetamine, norephedrine, an acid-labile precursor of benzyl methyl ketone and an unknown weakly acidic metabolite. The output of norephedrine was dose-dependent, being about 19% on the higher dose and about 1% on the lower dose. 5. Marked species differences in the metabolism of methamphetamine were observed. The main reaction in the rat was aromatic hydroxylation, in the guinea pig demethylation and deamination, whereas in man much of the drug, possibly one-half, was excreted unchanged.

Animals↗

PubMed1972

Norephedrines as metabolites of ( 14 C)amphetamine in urine in man.

(+/-)-[(14)C]Amphetamine sulphate (20mg) was administered orally to each of two human male subjects, and 80-85% of the (14)C was excreted in the urine in 2 days. The metabolites in the first day's urine were examined quantitatively. Apart from the metabolites previously described (Dring et al., 1970), norephedrine (2.2 and 2.6% of dose in the two subjects respectively) and 4-hydroxynorephedrine (0.3 and 0.4% of dose in the two subjects respectively) were also found.

Amino Alcohols↗

PubMed1972

Biliary excretion of amphetamine and methamphetamine in the rat.

1. (14)C-labelled amphetamine and methamphetamine were injected into rats cannulated at the bile duct under thiopentone anaesthesia and the output of their metabolites in urine and bile was determined. 2. With amphetamine, 69% of the (14)C was excreted in the urine and 16% in the bile in 24h. The main metabolite in bile was the glucuronide of 4-hydroxyamphetamine. The output of unchanged amphetamine was much greater in cannulated rats than in intact rats. 3. With methamphetamine, 54% of the (14)C appeared in the urine and 18% in the bile. The main metabolite in the bile was the glucuronide of 4-hydroxynorephedrine. The output of amphetamine, a metabolite of methamphetamine, was much greater in cannulated rats than in intact rats. 4. Evidence has been obtained for the enterohepatic circulation of certain amphetamine and methamphetamine metabolites in the rat. 5. Thiopentone anaesthesia appeared to inhibit the ring hydroxylation of amphetamine administered as such or formed as a metabolite of methamphetamine.

Amphetamine↗

PubMed1972

The metabolites of cyclohexylamine in man and certain animals.

1. [1-(14)C]Cyclohexylamine hydrochloride was synthesized and given orally or intraperitoneally to rats, rabbits and guinea pigs (dose 50-500mg/kg) and orally to humans (dose 25 or 200mg/person). The (14)C is excreted mainly in the urine, most of the excretion occurring in the first day after dosing. Only small amounts (1-7%) are found in the faeces. 2. In the rat, guinea pig and man, the amine is largely excreted unchanged, only 4-5% of the dose being metabolized in 24h in the rat and guinea pig and 1-2% in man. In the rabbit about two-thirds of the dose is excreted unchanged and about 30% is metabolized. 3. In the rat, five minor metabolites were found, namely cyclohexanol (0.05%), trans-3- (2.2%), cis-4- (1.7%), trans-4- (0.5%) and cis-3-aminocyclohexanol (0.1% of the dose in 24h). 4. In the rabbit, eight metabolites were identified, namely cyclohexanol (9.3%), trans-cyclohexane-1,2-diol (4.7%), cyclohexanone (0.2%), cyclohexylhydroxylamine (0.2%) and trans-3- (11.3%), cis-3- (0.6%), trans-4- (0.4%) and cis-4-aminocyclohexanol (0.2%). 5. In the guinea pig, six minor metabolites were found, namely cyclohexanol (0.5%), trans-cyclohexane-1,2-diol (2.5%) and trans-3- (1.2%), cis-3- (0.2%), trans-4- (0.2%) and cis-4-aminocyclohexanol (0.2%). 6. In man only two metabolites were definitely identified, namely cyclohexanol (0.2%) and trans-cyclohexane-1,2-diol (1.4% of the dose), but man had been given a smaller dose (3mg/kg) than the other species (50mg/kg). 7. The hydroxylated metabolites of cyclohexylamine were excreted in the urine in both free and conjugated forms. 8. Although cyclohexylamine is metabolized to only a minor extent, in rats the metabolism was mainly through hydroxylation of the cyclohexane ring, in man by deamination and in guinea pigs and rabbits by ring hydroxylation and deamination.

Animals↗

PubMed1972

The fate of cyclamate in man and other species.

1. (14)C-labelled cyclamate has been administered to guinea pigs, rabbits, rats and humans. When given orally to these species on a cyclamate-free diet, cyclamate is excreted unchanged. In guinea pigs some 65% of a single dose is excreted in the urine and 30% in the faeces, the corresponding values for rats being 40 and 50%, for man, 30-50% and 40-60%, and for rabbits, 90 and 5%, the excretion being over a period of 2-3 days. 2. Cyclamate appears to be readily absorbed by rabbits but less readily by guinea pigs, rats and humans. 3. If these animals, including man, are placed on a diet containing cyclamate they develop the ability to convert orally administered cyclamate into cyclohexylamine and consequently into the metabolites of the latter. The extent to which this ability develops is variable, the development occurring more readily in rats than in rabbits or guinea pigs. In three human subjects, one developed the ability quite markedly in 10 days whereas two others did not in 30 days. Removal of the cyclamate from the diet caused a diminution in the ability to convert cyclamate into the amine. 4. In rats that had developed the ability to metabolize orally administered cyclamate, intraperitoneally injected cyclamate was not metabolized and was excreted unchanged in the urine. The biliary excretion of injected cyclamate in rats was very small, i.e. about 0.3% of the dose. 5. The ability of animals to convert cyclamate into cyclohexylamine appears to depend upon a continuous intake of cyclamate and on some factor in the gastrointestinal tract, probably the gut flora.

Animals↗

PubMed1972

The role of the gut flora in the metabolism of cyclamate.

1. [(14)C]Cyclamate was not metabolized when incubated with the liver, spleen, kidney or blood of rats of rabbits kept on a cyclamate-containing diet, and that had become converters of cyclamate into cyclohexylamine. 2. [(14)C]Cyclamate was converted into cyclohexylamine when incubated under anaerobic conditions with the contents of the caecum, colon or rectum or with the faeces of cyclamate-pretreated rats. Similar results were obtained with cyclamate-pretreated rabbits. With cyclamate-pretreated guinea pigs, which did not readily convert cyclamate into cyclohexylamine, the colon contents showed only low activity in this respect. 3. The faeces of a human converter of [(14)C]cyclamate into cyclohexylamine were also very active, but became less active when cyclamate was removed from his diet. 4. On subculturing the organisms from the contents of the colon and rectum of rats, the ability to convert cyclamate into cyclohexylamine was lost during three subcultures, but the loss of the activity was considerably decreased by subculturing in the presence of cyclamate. 5. Incubation of rat faeces in broths containing cyclamate increased their ability to metabolize cyclamate, but similar treatment of rabbit and human faeces suppressed this activity. 6. When rats are kept on a cyclamate diet the number of clostridia in the faeces increased considerably. In human dietary cyclamate did not appear to alter the counts of various faecal micro-organisms. 7. The gut organisms that appear to develop the ability to convert cyclamate into cyclohexylamine are clostridia in rats, enterobacteria in rabbits and enterococci in man. 8. [(14)C]Cyclohexylamine injected into the caecum or colon of rats is readily absorbed and excreted in the urine. 9. It appears that on continued intake of cyclamate the gut flora develop the ability to convert cyclamate into cyclohexylamine, which is then absorbed and excreted mainly in the urine, although a small proportion is metabolized to other compounds.

Animals↗

PubMed1972

Species variations in the threshold molecular-weight factor for the biliary excretion of organic anions.

1. The excretion in the bile and urine after intravenous injection of 16 organic anions having molecular weights between 355 and 752 was studied in female rats, guinea pigs and rabbits. 2. These compounds were mostly excreted unchanged, except for three of them, which were metabolized to a slight extent (<7% of dose). 3. The rat excreted all the compounds extensively (22-90% of dose) in the bile. 4. In guinea pigs four of the compounds with mol.wt. 355-403 were excreted in the bile to the extent of 7-16% of the dose, four with mol.wt. 407-465 to the extent of 25-44% and eight compounds with mol.wt. 479-752 to the extent of 44-100%. 5. In rabbits four compounds with mol.wt. 355-465 were excreted in the bile to the extent of 1-8% of the dose, two compounds with mol.wt. 479 and 495 to the extent of 24 and 22%, and six compounds with mol.wt. 505-752 to the extent of 31-94%. 6. These results, together with those of other investigations from this laboratory, are discussed and the conclusion is reached that there is a threshold molecular weight for appreciable biliary excretion (i.e. more than 10% of dose) of anions, which varies with species: about 325+/-50 for the rat, 400+/-50 for the guinea pig and 475+/-50 for the rabbit. 7. Anions with molecular weights greater than about 500 are extensively excreted in the bile of all three species. 8. That proportion of the dose of these compounds which is not excreted in the bile is excreted in the urine, and in the three species, bile and urine are complementary excretory pathways, urinary excretion being greatest for the compounds of lowest molecular weight and tending to decrease with increasing molecular weight. 9. Some implications of this interspecies variation in the molecular-weight requirement for extensive biliary excretion are discussed.

Animals↗

PubMed1972