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Determination of 5‐(3,4‐Dihydroxy‐1,5‐cyclohexadien‐1‐yl)‐5‐phenylhydantoin (Dihydrodiol) and Quantitative Studies of Phenytoin Metabolism in Man

A routine gas chromatographic assay for urinary 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), the major metabolite of phenytoin (PHT) in man, was adapted to allow quantitation of 5-(3-hydroxyphenyl)-5-phenylhydantoin (m-HPPH) as well. Calculation of the urinary concentration of the minor metabolite, 5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)-5-phenylhydantoin (dihydrodiol, DHD) is based on the observation that acid-catalyzed dehydration of DHD quantitatively yields a mixture of p-HPPH and m-HPPH in a reproducible molar ratio of 56:44 p-HPPH:m-HPPH and on the assumption that all m-HPPH found in urine after heating with acid has been derived from DHD. The urinary DHD content was verified by a “specific” method in which urine was incubated with β-glucuronidase and the released phenolic metabolites completely removed by extraction. Subsequent acid-catalyzed dehydration of the remaining DHD yielded p-HPPH and m-HPPH, from the sum of which the original DHD concentration in urine could be calculated. In all of the urine samples from PHT patients examined to date, there was close agreement between the DHD values obtained by the “specific” method and those calculated from m-HPPH in the simple acid-hydrolysis method. It can be inferred that much the greater part (> 90%) of m-HPPH found in human urine after acid treatment has been derived from DHD. All samples of urine from PHT patients examined have shown detectable quantities of DHD. The methods described here may be useful in a survey of PHT patients to reveal unusual patterns of PHT metabolism and to permit recognition of possible associations between such unusual patterns and the occurrence of adverse reactions.