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T H Williams

Publications and source records attributed to T H Williams.

150 records · Page 9Linked to original sources
PubMedDate not supplied

Identification of the urinary metabolites of 14C-bumetanide in the rat and their excretion by rats and dogs.

Unchanged bumetanide, 3-(n-butylamino)-4-phenoxy-5-sulfamoylbenzoic acid, and five metabolites were excreted in the urine of rats given 50 mg of 14C-labeled drug per kg intravenously. The metabolites, which were identified by mass spectrometry and/or nuclear magnetic resonance spectroscopy, arose by metabolic alteration of the n-butyl sidechain. In metabolites I-V, the butylamino group was converted to -NHCH2CH2CH2COOH, -NHCH2CH2CH2CH2OH,, -NHCH2CH2CHOHCH3, -NHCH2CH2CHOHCH2OH and -NH2, respectively. The total urinary and fecal excretion of labeled drug and metabolites after iv and oral administration of 14C-bumetanide was estimated in dogs given 0.5 mg/kg and in rats given 5 mg/kg. In the dog, the primary excretion product was unchanged drug, although evidence was obtained that the acyl glucuronide of bumetanide was secreted in dog bile. The major metabolite excreted by the rat was I, and negligible quantities of intact drug were excreted in the urine after oral or iv administration. Optical activity was found for the two metabolites that contained a chiral center (III and IV), indicating that they were formed by a stereoselective hydroxylation.

Administration, Oral↗
PubMedDate not supplied

The metabolism of (-)-3-phenoxy-N-methylmorphinan in dogs.

The disposition of radioactive (-)-3-phenoxy-N-methyl[2-3H]morphinan in dogs after oral administration has been investigated. Unchanged drug was not found in bile, urine, or feces. Excretion of total radioactivity in feces ranged from 67 to 78% of an oral dose. Two unconjugated metabolites were isolated from feces and identified by NMR and GC/MS. Both were substituted on the phenoxy group; they were found to be the p-hydroxy (pOH-PMM) and the m-methoxy-p-hydroxy (mOCH3-pOH-PMM) metabolites. Further, levorphanol and norlevorphanol were identified in feces both as free and conjugated metabolites, as well as a small amount of levomethorphan. Urine contained mostly unknown metabolites and conjugated levorphanol and pOH-PMM. Although the glucuronide of mOCH3-pOH-PMM was the major metabolite in bile, smaller amounts of the glucuronide and sulfate conjugated of both levorphanol and pOH-PMM were also found. Estimates for the total urinary and fecal excretion (as percentages of the dose) by two dogs for the five known metabolites were as follows: levorphanol, 18.8-21.5%; pOH-PMM, 14.4-20.6%; mOCH3-pOH-PMM, 14.9%; norlevorphanol, 2.8-6.1%; levomethorphan, 0.5%. Two of these metabolites, pOH-PMM and levorphanol, are potent analgesics.

Animals↗
PubMedDate not supplied

Metabolism of 13-cis-retinoic acid by a rat liver 9000g supernatant preparation.

The in vitro metabolites formed on incubation of 13-cis-retinoic acid (13-cis-RA, isotretinoin) with a 9000g rat liver supernatant system were isolated by HPLC and identified by their mass and NMR spectra. The major metabolic pathway was hydroxylation at C4 to give 4-hydroxy-13-cis-RA, which was rapidly oxidized to 4-oxo-13-cis-RA, the major isolated metabolite. Further metabolism of this 4-oxo metabolite led to two novel compounds, 2-hydroxy-4-oxo-13-cis-RA and 3-hydroxy-4-oxo-13-cis-RA. In addition, small amounts of 13-cis-RA and 4-oxo-13-cis-RA were enzymatically converted to their all-trans isomers. Support for these pathways was obtained by the metabolism of reference samples of 4-hydroxy-13-cis-RA, 4-oxo-13-cis-RA, all-trans-RA, and 4-oxo-all-trans-RA. The predominant formation of 4-oxo metabolites of 13-cis-RA in this in vitro rat system and the results from previously reported in vivo metabolism studies suggest that oxidation at C4 is a major metabolic pathway of 13-cis-RA in both rats and humans.

Animals↗
PubMedDate not supplied

Metabolism of an anxiolytic imidazobenzodiazepine by the dog.

14C-labeled 8-chloro-6-(2-chlorophenyl)-4H-imidazo [1,5a][1,4]-benzodiazepine-3-carboxamide hydrochloride, 1 X HCl, was administered iv to two dogs. 14C-1 X HCl was extensively metabolized; in one dog, only 2% of the administered radioactivity was excreted as unchanged 1. The 4-hydroxy derivative of 1, compound 2, accounted for an additional 5% of the dose. Three urinary metabolites were identified by enzyme hydrolysis and NMR spectroscopy as conjugates of the phenolic 3'-, 4'-, and 5'-hydroxy derivatives of 1. In both dogs, the 4'-hydroxy derivative was the major identified metabolite (21 and 15% of the dose). Oral administration of 100 mg/kg/day of unlabeled 1 to dogs for 11 weeks resulted in the excretion of four urinary metabolites, the conjugated 3'-hydroxy and 4'-hydroxy derivatives of both 1 and 2. This prominent excretion of conjugated phenolic metabolites does not fit the usual pattern of 1,4-benzodiazepine metabolism in the dog.

Animals↗