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

• Main Authors: Miaoran Ning, Liang Li, Jian Li, Zaiquan Li, Runtao Li, Tianyan Zhou, Wei Lu
• Format: Article
• Language: English
• Published: Elsevier 2012-04-01
• Series: Acta Pharmaceutica Sinica B
• Subjects: TM208; TM209; RLMs; CYP3A; Reversible inhibition; TDI; DDI
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211383512000238
• ISSN: 2211-3835; 2211-3843

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 (Kl) were 31.93±12.64 and 32.91±15.58 μM, respectively, and the maximum inactivation rates (kinact) were 0.03497±0.0069 and 0.07259±0.0172 min−1 respectively. These findings would provide useful in vitro information for future in vivo DDI studies on TM208 or TM209.