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

Aims To determine the induction effect of rifampicin on the activity of 4′-hydroxylase in poor metabolizers (PMs) with m[sub 1] 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 m[sub 1] mutation were chosen to take rifampicin 300 mg day[sup -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/m[sub 1] and wt/m[sub 2] ) (203.9±42.5% vs 69.6±4.1%). 0–8 h urinary mephenytoin S/R ratio of those PMs with m[sub 1] 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 m[sub 1] mutation of S-mephenytoin 4′-hydroxylation can be induced by rifampicin and the inducing effect of rifampicin on 4′-hydroxylase is gene dependent. [ABSTRACT FROM AUTHOR]