Evidence for Stereoselective Production of Phenytoin (5,5-Diphenylhydantoin) Arene Oxides in Man
Part of the
Advances in Experimental Medicine and Biology
book series (AEMB, volume 197)
Phenytoin (5,5-Diphenylhydantoin, PHT), a widely-used antiepileptic drug, is metabolized via arene oxides (AO), which have been implicated in teratogenesis and idiosyncratic reactions associated with the drug (Martz et al., 1977; Speilberg et al., 1981; Gerson et al., 1983). PHT is a prochiral molecule and can be stereoselectively metabolized on either the pro-S- or pro-R- phenyl substituents to arene oxides, designated as (S)- or (R)-AO (Figure 1). As PHT arene oxides have not yet proved amenable to isolation and characterization, determination of stereochemistry of PHT AO’s has to be by indirect determination of the stereochemistry of the corresponding diastereomeric trans-dihydrodiols (5-(3,4-dihydroxy-1,5-cyclohexadien-l-yl)-5-phenylhydantoin, DHD) or enantiomeric p-phenols (5-(4-hydroxyphenyl)-5-phenylhydantoin, p-HPPH). Enantiomeric content will reflect arene oxide isomeric content only if all p-HPPH is formed via arene oxides and if the non-enzymatic rates of phenol formation (KR and KS) from AO’s are the same. Previous studies had indicated that the majority of human stereoselective metabolism of PHT is via the pro-Sphenyl substituent (Butler, 1957; Butler et al., 1976; Maguire et al., 1980; Chang and Glazko, 1982). In order to investigate variations in stereoselective metabolism, HPLC methods were employed to determine diastereomeric content of DHD and enantiomeric content of p-HPPH. These methods were used to estimate stereoselective metabolite production in volunteers and in a patient population.
KeywordsPhenyl Substituent Idiosyncratic Reaction Isomeric Content National Research Service Award Arene Oxide
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Butler, T.C., 1957, The Metabolic Conversion of 5,5-Diphenylhydantoin to 5-(p-hydroxyphenyl)-5-phenylhydantoin, J. Pharmacol. Exp. Ther.
, 119: 1.PubMedGoogle Scholar
Butler, T.C., Dudley, K.H., Johnson, D., and Roberts, S.B., 1976, Studies of the Metabolism of 5,5-Diphenylhydantoin Relating Principally to the Stereoselectivity of the Hydroxylation Products in Man and the Dog, J. Pharmacol. Exp. Ther.
, 199: 82.PubMedGoogle Scholar
Chang, T., and Glazko, A.J., 1982, Phenytoin: Biotransformation, In“Antiepileptic Drugs”(D.M. Woodbury, J.K. Penry and C.E. Pippenger, eds. ), Raven Press, N.Y., p. 209.Google Scholar
Claesen, M., Moustafa, M.A.A., Adline, J., Vandervorst, D., and Poupaert, J.H., 1982, Evidence for an Arene Oxide-NIH Shift Pathway in the Metabolic Conversion of Phenytoin to 5-(4-hydroxyphenyl)-5-phenylhydantoin in the Rat and in Man, Drug Metab. Dispos.
, 10: 667.PubMedGoogle Scholar
Gerson, W.T., Fine, D.G., Spielberg, S.P., and Sensenbrenner, L.L., 1983, Anticonvulsant-Induced Aplastic Anemia: Increased Susceptibility to Toxic Drug Metabolites In Vitro, Blood
, 61: 889.PubMedGoogle Scholar
Maguire, J.H., Kraus, B.L., Butler, T.C., and Dudley, K.H., 1979, Determination of 5-(3,4-dihydroxy-1,5-cyclohexadien-l-yl)-5-phenylhydantoin (Dihydrodiol), and Studies of Phenytoin Metabolism in Man, Ther. Drug Mon.
, 1: 359.CrossRefGoogle Scholar
Maguire, J.H., Butler, T.C., and Dudley, K.H., 1980, Absolute Configuration of Phenytoin Dihydrodiol Metabolites from Rat, Dog, and Human Urines, Drug Metab. Dispos.
, 8: 325.PubMedGoogle Scholar
Maguire, J.H., and Wilson, D.C., 1985, Urinary Dihydrodiol Metabolites of Phenytoin: HPLC Assay of Diastereomeric Composition, J. Chromatogr.
, 342: 323.PubMedCrossRefGoogle Scholar
Martz, F., Failinger, C., and Blake, D.A., 1977, Phenytoin Teratogenesis: Correlation between Embryopathic Effect and Covalent Binding of Putative Arene Oxide Metabolite in Gestational Tissue, J. Pharmacol. Exp. Ther.
, 203: 231.PubMedGoogle Scholar
Spielberg, S.P., Gordon, G.B., Blake, D.A., Goldstein, D.A., and Herlong, H.F., 1981, Predisposition of Phenytoin Hepatotoxicity Assessed In Vitro, New Eng. J. Med.
, 305: 722.PubMedCrossRefGoogle Scholar
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