1. Molecular modelling analysis of the
metabolism of phenytoin
Fazlul Huq
School of Biomedical
Sciences, Faculty of Health Sciences, The University of Sydney
E-mail :
f.huq@fhs.usyd.edu.au.
Abstract:
Phenytoin is a broad-spectrum
anticonvulsant that is widely used for the prevention and treatment of
seizure disorders. However, it provokes skin rash in 5 to 10% patients
and has been found to be teratogenic in various experimental animal
species. Epidemiological and clinical studies indicate that women who
have taken PHT during pregnancy have an increased risk of bearing a
child with a congenital anomaly. The toxic side effects of PHT may
result from its primary and secondary metabolites, rather than the
parent drug. PHT is metabolised by cytochrome P450 enzymes (CYP2C9 and
CYP2C19) primarily to inactive metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin
(4HPPH, in both R- and S-forms, accounting for about 80%
of all metabolites). 4HPPH may be further metabolized to hydroquinone
(HQ) that spontaneously oxidizes to semiquinone (SQ) and benzoquinone
(BZ) that bind covalently with proteins. Other minor metabolites in
man are: 5-(3-hydroxyphenyl)-5-phenylhydantoin (3HPPH) and 5-(3,4-dihydroxy-1,5-cyclohexadiene-1-yl)-5-phenylhydantoin
(DHD). Molecular modelling analyses show that PHT and most of its
metabolites do not differ widely in their kinetic lability except BQ
and SQ which have much lower values. BQ has the lowest HOMO-LUMO
energy difference and is therefore considered to be most toxic. The
differences in the formation heats suggest that BQ may be
thermodynamically unstable as well as its probable subjects to both
electrophilic and nucleophilic attacks.
Key words: Phenytoin, anticonvulsant,
Dilantin, teratogen, CYP2C9, molecular modelling
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