In vitro screening of reversible and time-dependent inhibition on CYP3A by TM208 and TM209 in rat liver microsomes

TM208 and TM209,dithiocarbamate derivatives with potential anti-cancer effects,were evaluated in reversible and time-dependent cytochrome P450(CYP)3A inhibition assays in rat liver microsomes using testosterone as probe substrate.Both compounds were found to be weak reversible inhibitors and moderate mechanism-based inhibitors of rat CYP3A.For reversible inhibition on rat CYP3A,the Ki values of competitive inhibition model were 12.10±1.75 and 13.94±1.31 μM,respectively.For time-dependent inhibition,the inactivation constants(K_(l))were 31.93±12.64 and 32.91±15.58 μM,respectively,and the maximum inactivation rates(kinact)were 0.0349770.0069 and 0.0725970.0172 min^(-1) respectively.These findings would provide useful in vitro information for future in vivo DDI studies on TM208 or TM209。