The induction effect of rifampicin on activity of mephenytoin 4′‐hydroxylase related to M1 mutation of CYP2C19 and gene dose

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Abstract
Aims 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. Methods 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. Results 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%. Conclusions 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.