Gender-related Pharmacokinetic Of Mifepristone/Metapristone And The Corresponding Mechanism Reseach Of Metapristone

Objective:Mifepristone(RU486)is marketed and used widely by women as an abortifacient,and used in clinical trials for psychotic depression and anticancer treatments.Metapristone is the most predominant biological active metabolite of mifepristone.In recent years,the study show that metapristone has the effect of preventing of tumor metastasis,which may be a good candidate drug to prevent tumor metastasis.Therefore,the purpose of this study was to investigate gender-related differences in pharmacokinetics of mifepristone or metapristone in the rat and beagle dogs and to study the mechanisms of action by which the gender difference in metapristone pharmacokinetics.Methods:Established UPLC-MS/MS analysis method for the determination of metapristone and its parent drug mifepristone in rat plasma,dog plasma,liver microsomes,respectively.We obtained plasma concentration at different time points in vivo by lavaging the male and female rats 22.5,45,90 mg/kg and intravenous 10 mg/kg,and lavaging the female and male beagle 5.62,11.25,22.5 mg/kg metapristone and mifepristone,then we used the non-compartmental model to analysis gender-related pharmacokinetic parameters of these drugs,so we calculated the oral bioavailability of rat.Metabolic stability experiment was studied to investigate the metabolic rate of metapristone6,9,13.5 ?M in vitro different gender rat liver microsomes.Chemical inhibitors and cDNA expressed CYP enzymes were analysed to identify the specific CYP450 enzymes involved in the biotransformation of 9 ?M metapristone by determining its remaining concentrations at a certain time.Results:UPLC-MS/MS methods were firstly developed for metapristone or mifepristone,with high accuracy and sensitivity.Metapristone and mifepristone were found to be rapidly absorbed and distributed,and slowly eliminated in gender difference rats.There was a linear relationship between AUC0-t and dose in male rats.Statistical analysis indicated that the plasma concentrations of metapristone and mifepristone in female rats were significantly higher than those in male rats and significant differences in F,AUC0-t,Vd and CL of metapristone and mifepristone were present between female and male groups.After oral administration of metapristone and mifepristone to beagle dogs,there were significant gender difference in Cmax,AUC0-t,Vd and CL in pharmacokinetic parameters.There was a linear relationship between AUC0-t and dose,coinciding with the pharmacokinetic results of rat,therefore there is no species difference.The metabolic stability showed that the metabolic rate of metapristone was slow and in female rats.liver microsomes significantly higher than those in male rats rats liver microsomes.Both chemical inhibitors and cDNA expressed CYP enzymes study revealed that ?-naphthoflavone(CYP1A2 inhibitor)and ketoconazole(CYP3A4 inhibitor)almost inhibited the biotransformation of metapristone,compared to the control group.CYP1A2 and CYP3A4 were mainly involved in the metabolism of metapristone in human liver microsomes.Conclusion:Pharmacokinetic parameters of metapristone and mifepristone had significant gender differences in rat and beagle dog.CYP1A2 and CYP3A4 were mainly involved in the metabolism of metapristone.In liver microsomes,sex differences of CYP1A2 and CYP3A4 in the metabolic activity were the reason of the gender difference in metapristone pharmacokinetics.