Stereoselective metabolism of mephenytoin in man

Stereoselectivity of aromatic hydroxylation and oxidative demethylation of mephenytoin has been investigated in normal, drug-free male subjects after single oral dose administration of enantiomerically radiolabeled pseudoracemic mephenytoin. Seven subjects received 23 μmol/kg of racemic mephenytoin containing 5 μCi of D-[¹⁴C]-S-mephenytoin and 45 μCi of L-[³H]mephenytoin. The major urinary metabolites were 3-methyl-5-(4-hydroxyphenyl)-5-ethylhydantoin(4-OH-M) and 5-phenyl-5-ethylhydantoin (PEH). Urinary excretion of 4-OH-M was rapid with a half-life of 3.8±0.7 hr and 46±5% of the racemic dose was recovered as 4-OH-M in 72 hr, of which 91±4% was formed from [¹⁴C]-S-mephenytoin. In contrast, urinary excretion of PEH was slow with only 3.0±1.4% of the racemic dose appearing in urine in the first 72 hr. In extended observations in two subjects, peak urinary excretion of PEH occurred between 48 and 72 hr and the subsequent rate of elimination half-lives were greater than 80 hr. From 0 to 72 hr, both ¹⁴C-S and ³H-R-enantiomers contributed to PEH; however, only [³H]-R-mephenytoin contributed to the later excretion of PEH. In two further subjects, reversal of the isotopic composition of the pseudoracemate did not influence the urinary excretion of either enantiomer. The tritium label in the 4-phenyl position of S-mephenytoin was retained in 4-OH-M, implying an NIH shift during aromatic hydroxylation. Thus, there is evidence of marked stereoselective differences in the metabolism of racemic mephenytoin. These differences suggest that R-mephenytoin is likely to contribute to the well described accumulation of PEH in plasma during chronic anticonvulsant therapy, whereas S-mephenytoin is rapidly eliminated through an oxidative process which has the potential for the production of reactive intermediate metabolites possibly of toxic importance.