Structure-activity relationships of phenytoin-like anticonvulsant drugs.

A limited series of compounds structurally related to phenytoin has been tested in the maximal electroshock seizure (MES) test in order to define the impact on their antiepileptic activity of reducing the ability to form a hydrogen bond. A net stepwise decrease of the anticonvulsant activity was observed when the hydantoin ring structure was altered into succinimide and pyrrolidinone and when these rings were N-methylated. The pharmacological data analyzed in terms of structure-activity relationships (SAR) indicate the importance of the capability of forming hydrogen bonds.

Evidence for an arene-3,4-oxide as a metabolic intermediate in the meta- and para-hydroxylation of phenytoin in the dog.

To investigate the potential involvement of an arene oxide-NIH shift pathway in the meta- and para-hydroxylation of phenytoin, (R,S)-5-(2-deuteriophenyl)-5-phenylhydantoin (2-2H-DPH), (R,S)-5-(3-deuteriophenyl)-5-phenylhydantoin (3-2H-DPH), and (R,S)-5-(4-deuteriophenyl)-5-phenylhydantoin (4-2H-DPH) were subjected to in vivo metabolic experiments in the dog. After enzymatic hydrolysis of the urine, meta- and para-hydroxy metabolites were isolated by HPLC and deuterium retentions were determined by GC/MS. The metahydroxy metabolites had 100, 52, and 80-82% retained of their initial deuterium content after oral administration of (R,S)-2-, 3-, and 4-2H-DPH, respectively.

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.

To determine whether the hydroxylation of 5,5-diphenylhydantoin (DPH) to 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) occurs by an arene oxide-NIH shift process, racemic 5-(4-deuteriophenyl)-5-phenylhydantoin (p-2H-DPH) was subjected to in vivo metabolic experiments in the rat and in man. After enzymatic hydrolysis of the urine, para-hydroxylated metabolites were separated by HPLC. Deuterium retention in the isolated metabolites determined by gas chromatography-mass spectrometry, was 68-72%.