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.
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002942:Circular Dichroism; D004285:Dogs; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D009905:Optical Rotatory Dispersion; D010672:Phenytoin / Q000031:analogs & derivatives* / Q000652:urine*; D051381:Rats; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism
C027363:5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)-5-phenylhydantoin; C027364:5-(3-hydroxyphenyl)-5-phenylhydantoin; D010672:Phenytoin