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).