Praeruptorin Compounds Exhibit Inhibition Towards the Metabolism of Lung Cancer Therapeutic Drug Irinotecan

Lung cancer has been widely considered to be one of the most common and severe types of cancers, and irinotecan is the common drug clinically used to treat lung cancer. Irinotecan undergoes two-step metabolic reaction, including carboxylesterase 2 (CES2)-catalyzed hydrolysis metabolism and UDPglucuronosyltransferase (UGT) 1A1 and 1A7-catalyzed glucuronidation reaction. This study aims to investigate the inhibition of praeruptorin compounds towards drug-metabolizing enzymes (DMEs) involved in the metabolism of irinotecan, including CES2, UGT1A1, and UGT1A7. In vitro human liver microsomes (HLMs)-catalyzed hydrolysis metabolism of fluorescein diacetate (FD) was used to investigate the inhibition of praeruptorin compounds on CES2, and in vitro recombinant UGTs-catalyzed glucuronidation metabolism of 4-methylumbelliferone (4-MU) was used to determine the inhibition of praeruptorin compounds on the activity of UGT1A1 and UGT1A7. 100 mu M of praeruptorin compounds were selected to determine the inhibition on the activity of CES2, UGT1A1, and UGT1A7. 100 mu M of praeruptorin C, D, and E inhibited approximately 60% activity of CES2 (p <.01). 100 mu M of praeruptorin C, D, and E showed negligible inhibition on the activity of UGT1A1. For UGT1A7, praeruptorin C showed strong inhibition potential on the activity of UGT1A7 (p < 0.01), but praeruptorin D and E did not show significant inhibition on the activity of UGT1A7. In conclusion, praeruptorin C, D, and E can alter the metabolic behavior of irinotecan through affecting the activity of CES2 or UGT1A7.