Molecular Modelling Analysis of the Metabolism of Phenytoin
Phenytoin (PHT, also known as Dilantin) 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 catechol that spontaneously oxidizes to semiquinone and quinone species 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 Q and SQ which have much lower values. Q has the lowest HOMO-LUMO energy difference and is therefore considered to be most toxic. The differences in heats of formation suggest that Q may be thermodynamically unstable as well that may be subject to both electrophilic and nucleophilic attack.
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