Effect of DA-9801 on the Expression of Drug-metabolizing Enzymes and Transporters in Human Hepatocytes

Abstract

DA-9801, a mixed extract of Dioscoreae japonica and Dioscorea nipponica Makino, is awaiting phase 3 clinical study for the prevention or treatment of diabetic neuropathy in USA. To investigate whether DA-9801 acts as a perpetrator in drug interactions or not, we evaluated the mRNA induction of phase I and II drug metabolizing enzymes, including cyto-chrome P450 (CYP), UDP-glucuronosyltransferases (UGT) and sulfotransferases (SULT), and drug transporters. The mRNA levels of phase I and II enzymes and transporters were analyzed by real-time PCR using three different cryo-preserved human hepatocytes using specific primer and probe primer sets. We found that no significant alteration of the mRNA expression was observed in phase I enzymes including CYP1A2, CYP3A4, CYP2B6, CYP2C8, and CYP2C9, phase II enzymes such as UGT1A1, UGT1A4, UGT1A9, UGT2B7 and SULT2A1, and drug transporters including p-glycoprotein, MRP2, BCRP and OCT1 by DA-9801 treatment compared with vehicle treated control cells. Moreover, we found that CYP1A2-catalyzed phenacetin O-deethylase, CYP2B6-catalyzed bupropion hydroxylase, and CYP3A4-catalyzed midazolam 1’-hydroxylase activities were not interfered by DA-9801 in cryopreserved human hepatocytes. These results suggested that DA-9801 might not cause pharmacokinetic-based drug interactions with concurrent drugs which are the substrates of these drug metabolizing enzymes and transporters in humans.