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.