CLINICAL PHARMACOLOGY
Mephenytoin exhibits pharmacologic effects similar to both phenytoin and the barbiturates in antagonizing experimental seizures in laboratory animals. Mephenytoin produces behavioral and electroencephalographic effects in people which are similar to those produced by barbiturates.
The absorption of mephenytoin given orally as a solution of the racemic drug is rapid. Mephenytoin is metabolized stereoselectively. The S-enantiomer is preferentially hydroxylated to give 5-ethyl-3-methyl-5-(4-hydroxyphenyl)-2,4-imidazolidinedione (S-4´-hydroxymephenytoin). The R-enantiomer is primarily N-demethylated to give 5-ethyl-5-phenyl-2,4-imidazolidinedione (R-phenylethylhydantoin) [R-PEH], the active metabolite. Following simultaneous administration of 14C-S-mephenytoin and 3H-R-mephenytoin, 95±3% of the administered 14C radioactivity was recovered in the urine 24 hours after dosing in the form of S-4´-hydroxymephenytoin, while in the same period, only 3% of the administered 3H radioactivity was found in the urine.
R-mephenytoin reaches peak concentration in about 1.5 hours. Both R-mephenytoin and its active metabolite R-PEH displayed linear kinetics in the dose range of 50-200 mg. The steady state volume of distribution for R-mephenytoin is about 1.4 L/kg. The mean elimination half-life of R-mephenytoin is 73±30 hours and for the metabolite R-PEH is 127±31 hours. The relative bioavailability of R-mephenytoin (Tablet/Solution) is 104%.
In several populations, a genetic impairment which decreases the efficiency of aromatic hydroxylation of S-mephenytoin, but not the N-demethylation of R-mephenytoin, has been established. Poor metabolizers occur with a frequency of 2%-5% in the Caucasian population and 18%-23% in Japanese subjects.
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