The introduction of chloral hydrate into medical practice.
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Chloral Hydrate↗
Biomedical subjects
T C Butler
Publications and source records attributed to T C Butler.
Absolute configurations of the dihydrodiol metabolites of 5,5-diphenylhydantoin (phenytoin) from rat, dog, and human urine.
Dihydrodiol metabolites (DHD) of phenytoin (PHT) have been extracted from the urine of rats and dogs, and from that of a patient on chronic PHT therapy. The crystalline rat DHD was dehydrated to give a mixture of (S)-5-(4-hydroxyphenyl)-5-phenylhydantoin and (S)-5-(3-hydroxyphenyl)-5-phenylhydantoin. The absolute configuration of C5 of the hydantoin ring of the DHD can accordingly be assigned as (S). Circular dichroism studies allowed further assignment of absolute configuration to the crystalline rat DHD, the metabolite being identified as (5S)-5-[(3R,4R)-3,4-dihydroxy-1,5-cyclohexadien-1-yl]-5-phenylhydantoin, (5S)-DHD. The human DHD metabolite was identical with the (5S)-DHD. The DHD from dog urine was found to be a mixture of diastereoisomers; the major component was identified as (5R)-5-[(3R,4R)-3,4-dihydroxy-1,5-cyclohexadien-1-yl]-5-phenylhydantoin, (5R)-DHD, and the minor diastereoisomer was identified as (5S)-DHD. The ratio (5R)-DHD/(5S)-DHD was approximately 2. A comparison of the absolute configurations of phenolic metabolites of PHT and of the DHD's offered a basis for speculation as to stereochemical aspects of PHT metabolism in the rat, dog, and man.
Animals↗
Stereochemical aspects of the metabolism of 5-ethyl-5-phenylhydantoin (Nirvanol) in the dog.
Enantiomers of 5-ethyl-5-phenylhydantoin (EPH) were administered to dogs, and urinary metabolites were quantitated. After administration of (R)-EPH, the urinary products included unchanged drug, 5-ethyl-5-(4-hydroxyphenyl)hydantoin (p-EHPH), 5-ethyl-5-(3-hydroxyphenyl)hydantoin (m-EHPH), and an N-glucuronide of EPH. Administration of (S)-EPH gave urinary products consisting of unchanged drug, p-EHPH, m-EHPH, an N-glucuronide of EPH, and a dihydrodiol metabolite, which has been isolated and identified as (5 S)-5-[(3R,4R)-3,4-dihydroxy-1,5-cyclohexadien-1-yl]-5-ethylhydantoin. The levorotatory isomers of p- and m-EHPH have been assigned the (R)-configuration. An unidentified metabolite of EPH has been detected through its reactivity under basic conditions to yield 2-ethyl-2-phenylhydantoic acid, which can be cyclized with acid to EPH. Quantitative studies of the disposition of single oral doses of (R)-, (S)-, and (RS)-EPH by these metabolic routes suggest that the metabolism of one enantiomer is unaffected by the presence of the other enantiomer. Stereoselectivities of metabolic pathways are discussed in relation to stereoselectivities observed for phenytoin metabolism in the dog.
Animals↗
5-ethyl-5-phenylhydantoin N-glucuronide, the major urinary metabolite of 5-ethyl-5-phenylhydantoin (Nirvanol) in the dog.
A water-soluble metabolite, isolated from the urine of dogs given (S)-5-ethyl-5-phenylhydantoin [(S)-EPH], has been identified as 1-deoxy-1-[(5S)-5-ethyl-5-phenylhydantoin-3-yl] beta-D-glucopyranuronate [(S)-EPH N-glucuronide]. EPH N-glucuronide did not release the aglycone upon acid or beta-glucuronidase treatment, but incubation in alkaline solution (pH 12-13) readily formed 2-ethyl-2-phenylhydantoic acid (EPHA). The EPHA so formed could be quantitatively cyclized to EPH. With the knowledge of the conversion efficiency of EPH N-glucuronide to EPHA, a quantitative GLC assay for the metabolite was developed. EPH N-glucuronide was found to be the major urinary metabolite after administration to dogs of either (R)-, (S)-, or (RS)-EPH.
Animals↗