rifampin and 4-hydroxymephenytoin

To determine the induction effect of rifampicin on the activity of 4'-hydroxylase in poor metabolizers (PMs) with m1 mutation of S-mephenytoin 4'-hydroxylation and the relationship of the effect with gene dose.. Seven extensive metabolizers (EMs) of S-mephenytoin 4'-hydroxylation and five PMs with m1 mutation were chosen to take rifampicin 300 mg day(-1) orally for 22 days. Prior to and after rifampicin treatment, each subject was given racemic mephenytoin 100 mg. The 4'-hydroxymephenytoin (4'-OH-MP) excreted in the 0-24 h urine and mephenytoin S/R ratio in the 0-8 h urine were determined by h.p.l.c. and GC, respectively.. In all EMs, the excretion of 4'-OH-MP in the 0-24 h urine was increased by 146.4 +/- 17.9%, 0-8 h urinary mephenytoin S/R ratio was decreased by 77.3 +/- 8.8%, the percentage increase in the 0-24 h excretion of 4'-OH-MP in those CYP2C19 homozygous (wt/wt) was greater than that in those heterozygous (wt/m1 and wt/m2) (203.9 +/- 42.5% vs 69.6 +/- 4.1%). 0-8 h urinary mephenytoin S/R ratio of those PMs with m1 mutation was decreased by 9.6%, the amount of 4'-OH-MP excreted in the 0-24 h urine was increased by 80.1 +/- 48.0%.. The activity of 4'-hydroxylase of PMs with m1 mutation of S-mephenytoin 4'-hydroxylation can be induced by rifampicin and the inducing effect of rifampicin on 4'-hydroxylase is gene dependent.

Topics: Adult; Antibiotics, Antitubercular; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C19; Cytochrome P-450 Enzyme System; Enzyme Induction; Humans; Hydroxylation; Male; Mephenytoin; Mixed Function Oxygenases; Mutation; Rifampin; Stereoisomerism

Studies were performed in 13 healthy subjects to determine whether treatment with rifampicin results in induction of the metabolism of mephenytoin. Daily dosing with 600 mg rifampicin for 22 days caused a three to eightfold increase in the 0-8 h urinary R/S ratio of mephenytoin following oral administration (100 mg) of racemic drug to extensive metabolizers of the anticonvulsant. This was accompanied by a 40 to 180% increase in the 0-8 h urinary excretion of the 4'-hydroxy metabolite. Four weeks after discontinuing rifampicin, both metabolic indices had returned to their baseline values. By contrast, rifampicin had no effect on either measures of metabolism in subjects of the poor metabolizer phenotype. Thus, it appears that the activity of the enzyme (P-450 MP) mediating the genetically determined 4'-hydroxylation of S-mephenytoin can be significantly modulated by enzyme inducing agents such as rifampicin and possibly environmental agents with a similar ability.

Topics: Adult; Female; Humans; Hydroxylation; Male; Mephenytoin; Middle Aged; Phenotype; Rifampin