THE INDUCTION EFFECT OF RIFAMPICIN ON ACTIVITY OF MEPHENYTOIN 4'-HYDROXYLASE RELATED TO M-1 MUTATION OF CYP2C19 AND GENE DOSE

Aims To determine the induction effect of rifampicin on the activity o f 4'-hydroxylase in poor metabolizers (PMs) with mi mutation of S-meph enytoin 4'-hydroxylation and the relationship of the effect with gene dose. Methods Seven extensive metabolizers (EMs) of S-mephenytoin 4'-h ydroxylation and five PMs with mi mutation were chosen to take rifampi cin 300 mg day(-1) orally for 22 days. Prior to and after rifampicin t reatment, each subject was given racemic mephenytoin 100 mg. The 4'-hy droxymephenytoin (4'-OH-MP) excreted in the 0-24 h urine and mephenyto in S/R ratio in the 0-8 h urine were determined by h.p.l.c. and GC, re spectively. Results In all EMs, the excretion of 4'-OH-MP in the 0-24 h urine was increased by 146.4 +/- 17.9%, 0-8h 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 g reater than that in those heterozygous (wt/m(1) and wt/m(2)) (203.9 +/ - 42.5% vs 69.6 +/- 4.1%). 0-8 h urinary mephenytoin S/R ratio of thos e PMs with mi mutation was decreased by 9.6%, the amount of 4'-OH-MP e xcreted in the 0-24 h urine was increased by 80.1 +/- 48.0%. Conclusio ns The activity of 4'-hydroxylase of PMs with mi mutation of S-mepheny toin 4'-hydroxylation can be induced by rifampicin and the inducing ef fect of rifampicin on 4'-hydroxylase is gene dependent.