R. T. Williams

The Fate of [14C]Phenol in Various Species

1. [14C]Phenol has been administered to man (dose, 0.01 mg/kg) and 18 animal species (25 mg/kg) and the urine examined for metabolites by radiochromatogram scanning.2. In three men 90% of an oral dose was excreted in 24 h mainly as phenylsulphate (77% of 24 h excretion) and phenylglucuronide (16%) with very small amounts of quinol sulphate and glucuronide.3. Four metabolites, the sulphates and glucuronides of phenol and quinol, were found in the urine of the rodents, the rat, mouse, jerboa, gerbil, hamster, lemming and guinea-pig after an oral dose of phenol.4. Three metabolites were excreted by some species, namely, phenol and quinol glucuronides and phenylsulphate by the squirrel monkey and capuchin monkey, and phenol and quinol sulphates and phenylglucuronide by the ferret, dog, hedgehog and rabbit.5. Two metabolites were excreted by the rhesus monkey, fruit bat and hen (phenylsulphate and phenylglucuronide) and by the cat (phenylsulphate and quinol sulphate). One metabolite (phenylglucuronide) only wa...

The Role of the Gut Flora in the Metabolism of Prontosil and Neoprontosil in the Rat

1. The urinary excretion of total sulphanilamide (free and acetylated) in rats receiving Prontosil or Neoprontosil orally is considerably reduced when the rats are treated with antibiotics to suppress their intestinal flora. The absorption and metabolism of sulphanilamide are unaffected by such treatment with antibiotics.2. The lipid-soluble Prontosil after oral or intraperitoneal administration is partly excreted in the bile as a polar conjugate, apparently an N-glucuronide, and this drug appears to be converted into sulphanilamide partly by metabolism by the body tissues and partly by enterofloral metabolism.3. The polar, water-soluble Neoprontosil is poorly absorbed from the intestine and when given orally is largely reduced to sulphanilamide by the gut flora before absorption. When given intraperitoneally, a large proportion (up to 70%) of the drug is excreted in the bile unchanged, and it would appear that only a small proportion of the drug (ca. 20%) is converted to sulphanilamide in the tissues, th...

The Fate of [14C]Saccharin in Man, Rat and Rabbit and of 2-Sulphamoyl[14C]benzoic Acid in the Rat

1. [14C]Saccharin administered orally was excreted entirely unchanged by rats on a normal diet and by rats on a 1% and 5% saccharin diet for up to 12 months. Some 90% dose was excreted in 24 h, about 70–80% in urine and 10–20% in faeces. No metabolite was detected in the excreta by chromatography or reverse isotope dilution. No 14CO2 was found in the expired air and no 14CO32- or 2-sulphamoylbenzoic acid in the urine.2. When [14C]saccharin was injected into bile-duct cannulated rats kept on a normal diet or on a 1% saccharin diet for 19 and 23 months, 0.1–0.3% dose appeared in the bile in 3 h and no more at 24 h after dosing. Most of the saccharin was excreted in the urine, 0.6% appearing in the faeces.3. [14C]Saccharin given orally to rabbits kept on untreated water and on water containing 1% saccharin for 6 months was excreted unchanged, 60–80% in 24 h, with 70% in urine and 3–11% in faeces.4. [3-14C]Saccharin taken orally was excreted unchanged mainly in urine (85–92% in 24 h) by 3 adult humans both be...

The Conjugation of 1- and 2-Naphthols and other Phenols in the Cat and Pig

[1-14C]-Naphthol and [8-14C]2-naphthol (25 mg/kg) injected into cats were excreted in the urine almost entirely as sulphate conjugates. Only about 1–2% of the dose appeared as naphthylglucuronides. 1-Naphthol gave entirely 1-naphthylsulphate whereas 2-naphthol gave 2-naphthylsulphate and an unidentified hydroxynaphthylsulphate in the ratio of 4 : 1.When [8-14C]2-naphthol was injected into pigs (dose 25 mg/kg) it was excreted mainly as 2-naphthylglucuronide with a small amount of 2-naphthyl sulphate (ratio about 15 : 1), but when [1-14C]1-naphthol was injected, 1-naphthylglucuronide and 1-naphthylsulphate were excreted in the ratio of 2 : 1. The pig, therefore, formed substantial amounts of 1-naphthylsulphate but not of 2-naphthylsulphate.The cat excreted injected [14C]morphine mainly as morphine 3-sulphate and [14C]phenacetin as 4-acetamidophenylsulphate, but injected [3H]phenolphthalein was excreted as the glucuronide and sulphate in the ratio of 3 : 2. The cat, therefore, formed substantial amounts of p...

The Metabolism of Carbenoxolone in the Rat

1. [3H]18β-Glycyrrhetic acid administered orally to rats is absorbed from the stomach and excreted in the bile as glycyrrhetyl-30-glucuronide, glycyrrhetic acid-3-O-hydrogen sulphate and a second glucuronide conjugate, probably glycyrrhetic acid 3-O-glucuronide. 18β-Glycyrrhetic acid undergoes entero-hepatic circulation in the rat.2. Carbenoxolone labelled with 14C in the succinate moiety administered orally to intact rats gives 71% dose as 14CO2, 26% in the faeces and 2% in the urine, and intraperitoneally gives 68% as 14CO2. When administered to rats with biliary cannulae, oral dosage gave: 53% 14CO2, 25% in bile, 6% in faeces and 2% in urine; intraperitoneal dosage gave: 12% 14CO2, 54% in bile, 2% in urine and none in faeces. These figures suggest that hydrolysis of [14C] carbenoxolone into [14C]succinate plus 18β-glycyrrhetic acid occurs in the gastrointestinal tract before absorption, the [14C]succinate being further metabolized to 14CO2.3. After oral dosage with [14C]carbenoxolone the bile contains ...

The metabolism of (-)-ephedrine in man.

SummaryThe metabolic fate of orally administered (−)-[14C]-ephedrine has been studied in 3 human subjects and the urinary excretion of metabolites determined quantitatively by solvent extraction, paper chromatography and reverse isotope dilution procedures. Following an oral dose of the drug (0.35 mg/kg, 1.6 µCi), 97% of the dose was excreted in the urine within 48 h, 88% in the first 24 h. Unchanged drug was the major urinary excretory product (53–74%), with N-demethylation occurring to a variable extent (8–20%) although there was little interindividual variation in urine pH. Oxidative deamination was also variable (4–13%); the main identified products of this were benzoic acid (free and conjugated) and 1,2-dihydroxy-1-phenylpropane (free and conjugated). No phenolic metabolites could be detected, and thus it would appear that these compounds cannot be implicated in the acquisition of tolerance to ephedrine which can occur on repeated dosage.

Molecular Weight and Chemical Structure as Factors in the Biliary Excretion of Sulphonamides in the Rat

1. Biliary excretion in biliary-cannulated female rats of 23 derivatives of sulphanilamide, in which the N4-position is substituted with various carboxyacyl groups and the N1-position with acetyl or 2-thiazole, has been studied.2. Six compounds having molecular weights in the range 172–314 were poorly excreted in the bile ( 5–10% of dose).3. Above the threshold mol. wt., biliary excretion is high (20–70% of dose) but there is no direct relationship between the two, as the extent of biliary excretion is not directly proportional to mol. wt.4. There is no direct relationship between the extent of biliary excretion and the relative lipid solubilities as measured by distribution ratios between buffer pH 7.4 and organic solvents. Nevertheless th...

The metabolism of amphetamine in dependent subjects.

SummaryThe metabolism of (+)-[14C] amphetamine has been studied in two women who had been taking 90–100 mg of Dexedrine ((+)amphetamine sulphate; Smith, Kline & French) daily for several years but who showed no evidence of overt amphetamine toxicity. The urinary metabolites were identified, estimated and compared with the results previously obtained from two drug naive male subjects who had received 20 mg of (±)amphetamine (Caldwellet al., (1972b). The same metabolites were found, but the dependent subjects excreted in 24 h more unchanged amphetamine (about 30% of dose) than the naive subjects (20%). This may be a reflection of the dose, which in dependent subjects was five times that of naive subjects. The dependent subjects excreted in 24 h slightly more norephedrine (2.9, 4.1% of dose) and 4′-hydroxynorephedrine (1.1, 1.6%) than the naive subjects (norephedrine, 2.2, 2.6%; 4′-hydroxynorephedrine, 0.3, 0.4%), but the difference in percentage of dose may not be significant. However, in absolute terms the dependent subjects are producing at least five times as much norephedrines as the naive subjects because of the larger dose.

The conjugation of phenol, benzoic acid, 1-naphthylacetic acid and sulphadimethoxine in the lion, civet and genet.

In the domestic cat (FeZis catus) phenol is converted mainly to phenylsulphate with only small amounts of phenylglucuronide [l] . The cat’s ability to form the glucuronides of foreign compounds is low compared with other species [2] and it forms little or no glucuronide with phenol [I], benzoic acid [3], sulphadimethoxine [4] , or 1-naphthylacetic acid [5]. It was of interest therefore to find out whether catlike animals were similar to the domestic cat. The above four compounds were administered to weaned lion cubs (Panthera Zeo) and adult African civets (Viverra civet&) and forest genets (Genetru par&m) and their urine examined for metabolites. These animals showed little or no glucuronide formation with these compounds and they excreted phenol almost entirely as phenylsulphate, benzoic acid mainly as hippuric acid, 1-naphthylacetic acid as the glycine conjugate and sulphadimethoxine as such and as the N4-acetyl derivative. As far as conjugation is concerned, these compounds behave in the lion, civet and genet much as they do in the domestic cat.

The Conjugation of Indolylacetic Acid in Man, Monkeys and other Species

Indol-3-yl[2-14C]acetic acid has been administered to 18 species of animals including man, and the urinary metabolites examined by radiochromatogram scanning. Man received 500 mg orally and the other animals 100 mg/kg by intraperitoneal injection.In most species, 50–90% of the administered 14C was excreted in the urine in 48 h. 14–76% of the indolylacetic acid was excreted unchanged in 48 h.In man, the 14C excreted in 48 h consisted of about 50% unchanged indolylacetic acid, 30% indolylacetylglucuronide and 10–20% indolylacetyl-glutamine. No glycine conjugate was detected.The glutamine conjugate was excreted only by the Old World (3 species) and New World (3 species) monkeys and man.The glycine conjugate was excreted by all species (13) except man, Old World monkeys and the pigeon. The three species of New World monkeys formed both the glutamine and glycine conjugates.Taurine conjugation of indolylacetic acid was studied in the green monkey, the squirrel monkey, the capuchin monkey, the ferret and pigeon....