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.