Metapristone　is　the　primary　metabolite　of　the　abortifacient　mifepristone　(RU486),　and　is　being　developed　as　a　safe　and　effective　cancer　metastatic　chemopreventive　agent　for　both　sexes.　Here,　we　systematically　investigated　the　sex-related　pharmacokinetics　of　metapristone　in　both　rats　and　dogs,　and　explored　the　related　mechanisms　of　actions.　Administration　of　metapristone　to　rats　and　dogs　showed　that　plasma　concentrations　of　metapristone　(AUC,　C-max)　were　significantly　higher　in　female　dogs　and　rats　than　in　males.　The　sex-related　differences　in　pharmacokinetics　become　more　significant　after　ten　consecutive　days　of　oral　administration.　Female　liver　microsomes　metabolized　metapristone　significantly　slower　than　the　male　ones.　The　results　from　P450　reaction　phenotyping　using　recombinant　cDNA-expressed　human　CYPs　in　conjunction　with　specific　CYP　inhibitors　suggested　that　CYP1A2　and　CYP3A4　are　the　predominant　CYPs　involved　in　the　metapristone　metabolism,　which　were　further　confirmed　by　the　enhanced　protein　levels　of　CYP1A2　and　CYP3A4　induced　by　1-week　oral　administration　of　metapristone　to　rats.　The　highest　tissue　concentration　of　metapristone　was　found　in　the　liver.　The　study　demonstrates,　for　the　first　time,　the　sex-related　pharmacokinetics　of　metapristone,　and　reveals　that　activities　of　liver　microsomal　CYP1A2　and　CYP3A4　as　well　as　the　renal　clearance　are　primarily　responsible　for　the　sex-related　pharmacokinetics.