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

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.

journal_name

Br J Clin Pharmacol

authors

Feng HJ,Huang SL,Wang W,Zhou HH

doi

10.1046/j.1365-2125.1998.00643.x

subject

Has Abstract

pub_date

1998-01-01 00:00:00

pages

27-9

issue

1

eissn

0306-5251

issn

1365-2125

journal_volume

45

pub_type

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