PHENYTOIN METABOLISM IN MICE

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  • 1 January 1982
    • journal article
    • research article
    • Vol. 10  (2) , 156-160
Abstract
The effect of dose on the metabolism of phenytoin (5,5-diphenylhydantoin, DPH) [an anticonvulsant] was investigated. A single i.p. injection of 14C-DPH (1,20 or 100 mg/kg) was given to adult male mice, and urine and feces were collected over 72 h. DPH and its metabolites excreted in urine were separated and analyzed by high pressure liquid chromatography after .beta.-glucuronidase hydrolysis and extraction with ethyl acetate. The drug-related products measured in urine included DPH, 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), 5-(3,4-dihydroxy-1,5-cyclohexadien-1-yl)-5-phenylhydantoin (DHD), 5-(3-methoxy-4-hydroxyphenyl)-5-phenylhydantoin (OMCAT) and diphenylhydantoic acid (DPHA). The percentage of the dose appearing as unchanged DPH and DPHA increased with dose, whereas that excreted as OMCAT decreased at higher doses. The excretion of p-HPPH (.apprx. 30%) and DHD (.apprx. 12%) was independent of dose. The constant ratio of p-HPPH/DHD excreted in urine suggests that these metabolites have a common precursor, probably in arene oxide. Studies of the fate of DPH metabolites showed that a small fraction of a dose of p-HPPH or of DHD was converted to OMCAT. The catechol metabolite of DPH arises via 2 different mechanisms.