Discussion
Mifepristone is an important drug in the regimens for termination of early pregnancy, which has a high complete abortion rates in many countries.17, 18 However, 17.5% of patients in this study suffered from a failure outcome after a regimen of mifepristone and misoprostol. Pharmacogenomic is applied to the efficacy differences of mifepristone. The G2014A polymorphisms of estrogen receptor 1 is associated with the failure outcome in the mifepristone-induced abortion.19 In this study, we focused on the gene polymorphisms of th transporter and mebabolic enzyme of mifepristone, which affected the blood concentration of mifepristone.
MDR1 is a multiple specific efflux transporter of drugs and has a wide range of substrates including mifepristone.20 Genetic variations of MDR1 affect the amount and structure of mRNA and protein.21C3435T, C1236T and G2677T/A are the functional polymorphisms of MDR1. In vitro studies showed that C3435T genotype represented a main functional polymorphism, accounting for 1.5 to 2.0 fold changes in mRNA levels.22 C1236T could affect mRNA stability, whereas G2677T/A caused an amino acid substitution of Ala by Ser/Thr.21 Several researches demonstrated that gene polymorphisms of MDR1 connected with individual differences in drug response.23-25 Our study found that GG homozygotes of G2677T/A contributed to a higher success rates of medicine abortion, whereas the adverse reaction showed the opposite result. However, MDR1 C3435T and C1236T were no association with both efficacy and adverse reaction of mifepristone. P-gp is expressed in variable tissue distribution, such as intestine, hepatocytes and kidney.26 Thus, the absorption of mifepristone may be affected by the genetic variations of MDR1, causing the variability in blood concentrations of mifepristone. In the further analysis, G2677T/A but not C3435T and C1236T significantly influenced C/D ratio of both mifepristone and monodemethyl-mifepristone. This result could explain the observed difference in efficacy and adverse reaction of mifepristone due to G2677T/A.
CYP3A4 is a main member of the CYP family, which is highly expressed in intestine and liver.27At least of 50% of commonly used drugs are metabolized by CYP3A4, including mifepristone.28CYP3A4*1G has a high frequency in Han Chinese.29 In vitro, experiment showed that CYP3A4*1G caused lower enzymatic activities.30 However, controversy existed about the effect of CYP3A4*1G on the blood concentration and efficacy of drugs. Liu J et alfound that patients with GG homozygote have a higher imatinib mesylate plasma levels than that with GA and AA genotypes, but no effect of CYP3A4*1G on related adverse reactions.31 The Cmax values was significantly decreased in subjects with CYP3A4*1G genotype.32 In contrast, there was no association between CYP3A4*1G and amlodipine pharmacokinetic parameters.33 Yun Het al demonstrated that patients with the *1G/*1G homozygote have a higher reduction in diastolic blood pressure than that with other CYP3A4 genotypes.34 In our study, CYP3A4*1G contributed to a lower blood concentration of mifepristone, but not to blood concentration of monodemethyl-mifepristone. Interestingly, CYP3A4*1G was not linked with the efficacy and adverse reaction of mifepristone. Both mifepristone and monodemethyl -mifepristone have drug activity, in order to weaken the associations of CYP3A4*1G and blood concentration and adverse reactions incidence.
Blood concentration is closely associated with drug efficacy and drug adverse reaction. Mifepristone, as well as the metabolites are responsible for the biological actions of antiprogesterone.35With the exception of mifepristone, we also detected the concentration of monodemethyl-mifepristone which has the best affinity among three active metabolites. Our study confirmed that higher blood concentration of mifepristone and monodemethyl-mifepristone contributed to better clinical efficacy for medicine abortion, accompanied with a higher incidence of adverse reaction. After a correaction based on dose and weight, the C/D of mifepristone and monodemethyl-mifepristone was connected with clinical efficacy and adverse reaction of mifepristone, suggesting that a body weight-based dose might have substantive and clinical value for improving the success rates of medicine abortion.
In conclusion, the blood concentration of mifepristone and monodemethyl-mifepristone has a profound influence on clinical efficacy, implicating that dose individualization of mifepristone may be useful to improve the efficacy for medicine abortion. MDR1 G2677T/A and CYP3A4*1G caused the individual difference in the blood concentration of mifepristone. However, only MDR1 G2677T/A was associated with the efficacy and adverse reaction of mifepristone. These results suggested that G2677T/A made more contributions to mifepristone transport. Future studies with a large sample research will be needed to explore the interaction of MDR1 G2677T/A with CYP3A4*1G, in order to interpreting the finding of the present study.
Conflict of interest statement: The authors have no conflicts of interest to declare.
Funding information: This work was supported by the project of Fujian Maternity and Child Health Hospital (YCXM 20-35).