R. Tecwyn Williams

Taurine Conjugates as Metabolites of Arylacetic Acids in the Ferret

1. The pattern of conjugation in the ferret of 8 arylacetic acids and, for comparison, benzoic acid and 4-nitrobenzoic acid was examined. 2. The arylacetic acids, phenylacetic, 4-chloro- and 4-nitro phenylacetic, alpha-methylphenylacetic (hydratropic), 1- and 2-naphthylacetic and indol-3-ylacetic acids, were excreted in the urine as taurine and glycine conjugates. Diphenylacetic acid did not form an amino acid conjugate and was excreted as a glucuronide. 3. The taurine conjugate was the major metabolite of 4-nitrophenylacetic, alpha-methylphenylacetic, 1- and 2-naphthylacetic and indol-3-ylacetic acids, whereas the glycine conjugate was the major metabolite of phenylacetic and 4-chlorophenylacetic acids. Taurine conjugation did not occur with benzoic and 4-nitrobenzoic acids which were excreted as glycine and glucuronic acid conjugates. 4. Phenacetylglutamine and 4-hydroxyphenylacetic acid were minor urinary metabolites of phenylacetic in the ferret. 5. A number of taurine conjugates of aliphatic and aromatic acids were synthesized and their characterization and properties were studied. The role of taurine as an alternative to glycine in the metabolic conjugation of arylacetic acids is discussed.

The fate of lysergic acid di[14C]ethylamide ([14C]LSD) in the rat, guinea pig and rhesus monkey and of [14C]iso-LSD in rat

Abstract The qualitative and quantitative aspects of the metabolism and elimination of [14C]LSD in the rat, guinea pig and rhesus monkey have been investigated. Rats given an i.p. dose (1 mg/kg) excreted 73% of the 14C in the faeces, 16% in the urine and 3.4% in the expired air as 14CO2 in 96 hr. Guinea pigs similarly dosed, excreted 40% in the faeces, 28% (urine) and 18% (expired 14CO2) in 96 hr. Rhesus monkeys (0.15 mg/kg i.m.) eliminated 39% of the 14C in the urine and 23% in the faeces in 96 hr. Extensive biliary excretion of [14C]LSD occurred in both the rat and guinea pig. Bile duct-cannulated rats excreted 68% of an i.v. dose (1.33 mg/kg) in the bile in 5 hr and the guinea pig 52% in 6 hr. [14C]LSD is almost completely metabolised by all three species and little unchanged drug is excreted. The metabolites identified were 13- and 14-hydroxy-LSD and their glucuronic acid conjugates. 2-oxo-LSD. de-ethyl LSD and a naphthostyril derivative. There occur, however, important species differences in the nature and amounts of the various metabolites. In the rat and guinea pig the major metabolites were the glucuronic acid conjugates of 13- and 14-hydroxy-LSD which were found in both urine and bile. The guinea pig excreted significant amounts of 2-oxo-LSD in urine and bile. De-ethyl LSD was a minor urinary metabolite in both species. The metabolism of LSD appeared to be more complicated in the rhesus monkey. The urine contained at least nine metabolites of which four were identified as follows: 13- and 14-hydroxy-LSD (as glucuronic acid conjugates) de-ethyl LSD and a naphthostyril derivative. Unlike the rat and guinea pig the glucuronic acid conjugates of 13- and 14-hydroxy-LSD were only present in small amounts. Of the remaining five unidentified metabolites, three were major. The biliary metabolites of [14C]iso-LSD in the rat have been studied and been shown to be similar to those produced from [14C]LSD, namely 13- and 14-hydroxy-iso-LSD and their glucuronic acid conjugates and 2-oxo-iso-LSD.

Evidence against the involvement of false neurotransmitters in tolerance to amphetamine‐induced hyperthermia in the rat

ACHESON, G. H. & PEREIRA, S. A. (1946). BREESE, G. R., COOPER, B. R. & SMITH, R. D. (1973). In Frontiers in Catecholamine Research. Editors: Usdin, E. & Snyder, S. H., pp. 701-706. BRODIE, B. B., CHO, A . K. & GESSA, G. L. (1970). In Amphetamines and Related Compounds. Editors: Costa, E. & Garratini, S. pp. 217-230. BUETHIN, F. C., MIYA, T. S., BLAKE, D. E. & BOUSQUET, W. F. (1972). J. Pharmac. exp. Ther.,

The metabolism of lysergic acid di[14C]ethylamide ([14C]LSD) in the isolated perfused rat liver

Abstract Isolated female rat livers were perfused with a medium containing [ 14 C]LSD (1 mg and 0.13 μCi/g liver) and (+)-tartaric acid (15 mg). After 4.5 hr, the bile collected contained some 44% of the added radioactivity, the perfusate, 20% and the liver itself, 20%. The radioactive compounds in the bile were identified as 14-hydroxy-LSD glucuronide (21% of the added 14 C), 13-hydroxy-LSD glucuronide (8%), 2-oxo-LSD (7%) and unchanged LSD (1%). Those in the pooled perfusate and homogenised liver were unchanged LSD (18%), 2-oxo-LSD (5%), a naphthostyril derivative of LSD (4%; probably derived from 2-oxo-LSD), nor-LSD (4%), hydroxy-LSD glucuronides (3%) and de-ethyl-LSD (2%).

Species variations in the O-methylation of n-butyl 4-hydroxy-3,5-diiodobenzoate

Abstract The metabolism and excretion of orally administered or injected n -butyl 4-hydroxy-3,5-di[ 25 I]iodobenzoate has been studied in man, the rhesus, cynomolgus, squirrel and capuchin monkeys and the rat and rabbit. These species excreted most (about 80 per cent of dose) of the radioactivity in the urine over a period of 3 days except in the case of the squirrel and capuchin monkeys and the rat which excreted considerable amounts (17–30 per cent of dose) in the faeces. Four metabolites were characterized by thin-layer chromatography, gas-liquid chromatography-mass spectral analysis and by reverse isotope dilution and these were: 4-hydroxy-3,5-diiodobenzoic acid and its glycine conjugate and a product of O -methylation, namely, 3,5-diiodoanisic acid and its glycine derivative. There is a marked species difference in the excretion of 3,5-diiodoanisic acid for this metabolite was found only in the urine of the human subjects and the new and old World primate species and not in the rat and rabbit which excreted only 4-hydroxy-3,5-diiodobenzoic acid and its glycine conjugate. The excretion of the O -methylation product, 3,5-diiodoanisic acid, may be a further example of a metabolic reaction which is restricted in its occurrence to man and sub-human primates.

The fate of triphenyllead acetate in the rat

Triphenyllead acetate labeled with 14C or 3H in the benzene rings or with 203Pb has been synthesized and its fate in the rat has been partially elucidated. The compound is about 30 to 50 times more toxic to rats intraperitoneally than orally. Given orally (25 or 200 mg/kg) or intraperitoneally (2 mg/kg) most of the lead is excreted in the feces (up to 76% in 7 days). Sixty-five to eighty percent of the label of orally administered tri[14C]phenyllead acetate (25 mg/kg) is eliminated in 6 days, with 26, 27, or 21% occurring in the urine, feces, and expired air, respectively. The 14C in the urine was partially identified as quinol monosulfate (2%) and phenylsulfate (13%), that of the feces as unchanged triphenyllead acetate (4.5%), and that of the expired air as benzene (20%) and CO2 (1%). After an intraperitoneal injection of tri[3H]phenyllead acetate (2 mg/kg), 77% of the 3H was eliminated in 14 days, with 20, 51, and 7% being in the urine, feces, and expired air, respectively. The 14C in the urine collected after 3 days contained quinol monosulfate (<1%) and phenylsulfate (3%). Significant quantities of 3H appeared in the feces only on the third day, while after 4 days 25% of the dose was in the feces and half of this was unchanged triphenyllead acetate. About 1 to 2% of the dose was identified as benzene in the expired air. Following an intraperitoneal injection of 203Pb- or 3H-labeled triphenyllead acetate into bile duct-cannulated rats, about 4% of the 203Pb and 1.5% of the 3H was excreted in the bile in 1 day. In 4 days 7% of the 3H appeared in the bile. These results and studies of the stability of the compound under various conditions suggest that triphenyllead acetate is partially decomposed in the gut by nonenzymic mechanisms. This would account in part for the greater toxicity of the compound when administered by the ip route compared with the oral route.