Evidence for Stereoselective Production of Phenytoin (5,5-Diphenylhydantoin) Arene Oxides in Man

  • James H. Maguire
  • Judy S. McClanahan
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.


Phenyl Substituent Idiosyncratic Reaction Isomeric Content National Research Service Award Arene Oxide 
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Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • James H. Maguire
    • 1
  • Judy S. McClanahan
    • 1
  1. 1.Division of Medicinal Chemistry and Natural Products School of PharmacyUniversity of North CarolinaChapel HillUSA

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