INTRODUCTION
Mifepristone is a progesterone receptor (PR) antagonist that is the
first-line drug for the termination of early pregnancy. However, 5% -
17% of women did not pass the gestational sac spontaneously with either
a combination of mifepristone and misoprostol or mifepristone
alone.1,
2 There is a high variability of curative
effect within interindividual women on mifepristone, which may be
involved in gene polymorphisms of target tissues, drug disposition by
efflux transporters or metabolic enzymes, etc .3
Mifepristone is a substrate for P-glycoprotein (P-gp), which is an
ATP-dependent efflux pump and distributes in variable
tissue.4 Induction
of
P-gp in the intestine, kidney and surrounding tissues can reduce the
bioavailability of mifepristone,
increase renal clearance and reduce the distribution of surrounding
tissues.5,
6 Multidrug resistance gene 1 (MDR1) is
the encode gene of P-gp, which is highly polymorphic. Genetic variations
of MDR1 cause individual difference in pharmacokinetics and
bioavailability of
drugs.7 Taken together,
it suggests that gene polymorphisms of MDR1 maybe a key factor which
lead to the difference of the curative effect of mifepristone. The most
important polymorphisms of MDR1 are 3435C>T,
1236C>T and 2677G>T/A. The influence of these
gene polymorphisms on the efficacy of mifepristone is still uncertain.
Mifepristone is metabolized by
cytochrome P450 (CYP) enzymes,
mainly by isoenzyme
CYP3A4.8 CYP3A4 is the
predominant form of CYP in the adult liver, participating in the
oxidative metabolism of most
drugs.9,
10 It has been confirmed that genetic
variation alters
CYP3A4
metabolic activity.11CYP3A4*1G is the most common gene polymorphism among the Chinese
population, and influences most drug metabolism, such as tacrolimus and
rifampicin.12,
13 Thus, CYP3A4*1G maybe affect the
efficacy of mifepristone due to alteration of pharmacokinetics.
Mifepristone is metabolized into three metabolites which also have
pharmacological
activities.14 Compared
with mifepristone, the affinities of monodemethylated, didemethylated
and hydroxylated metabolites to PR are 61%, 45% and 48%,
respectively.15 The
blood
concentration
of mifepristone and
metabolites
might affect the efficacy in medicine abortion.
In this study,
we
evaluated the effects of gene polymorphisms of
MDR1
and CYP3A4 on the efficacy of mifepristone. And meanwhile, we clarified
the relationship between gene polymorphisms and blood concentration of
mifepristone and its monodemethylated metabolite on the efficacy of
mifepristone.