1. Anordrin (2α, 17α-diethynyl-A-nor-5α-androstane-2β, 17β-diol diproprionate) is post-coital contraceptive drug that is on the market in China for more than 30 years. This study aims to elucidate enzymes involved in anordrin hydrolysis, and to evaluate the significant role of carboxylesterases in anordrin hydrolysis in humans. 2. Human liver and intestinal microsomes, recombinant human carboxylesterase were selected as enzyme sources. In human liver microsomes, intrinsic clearance was 684 ± 83 μL/min/mg protein, which was considerably higher than the value of intestine microsomes (94.6 ± 13.3 μL/min/mg protein). Carboxylesterase (CES) 1 has more contribution than CES2 in human liver. 3. Inhibition studies were performed using representative esterase inhibitors to confirm esterase isoforms involved in anordrin hydrolysis. Simvastatin strongly inhibited hydrolytic process of anordrin in liver and intestine microsomes, with IC50 values of 10.9 ± 0.1 and 6.94 ± 0.03 μM, respectively. 4. The present study investigated for the first time hydrolytic enzyme phenotypes of anordrin. Anordrin is predominantly catalyzed by CES1 and CES2 to generate the main active metabolite, anordiol. Moreover, anordrin and its metabolite anordiol can be altered by esterase inhibitors, such as simvastatin, upon exposure in vivo.
Keywords: Anordiol; anordrin; carboxylesterase; drug–drug interaction; hydrolysis in humans.