In vitro metabolism of 4, 5-dimethoxycanthin-6-one by human liver microsomes and its inhibition on human CYP1A2

Aims: P. quassioides is a traditional Chinese medicine used for the treatment of gastroenteritis, snakebite, Infection and hypertension in China. 4, 5-dimethoxycanthin-6-one is one of the main active canthinone alkaloid isolated from P. quassioides. The aim of this work was to identify the cytochrome P (CYP) 450 enzymes responsible for the metabolism of 4, 5-dimethoxycanthin-6-one (DCO) and to evaluate the inhibitory effect of DCO on CYP activity in human liver microsomes (HLM) in vitro.

Materials and methods: the CYP isoforms responsible for DCO metabolism and the inhibitory effects of DCO on CYP activity was studied in HLM.

Key findings: The in vitro metabolic Enzyme of DCO was CYP3A4 (mediated the formation of metabolites M1-M5), CYP2C9 (mediated the formation of metabolites M1-M3, M6 and M8) and CYP2D6 (mediated the formation of metabolite M3) in HLM. Furthermore, the present work found that DCO uncompetitively inhibited CYP1A2-mediated phenacetin O-deethylation with an IC₅₀ value of 1.7μM and a Ki value of 2.6μM.

Significance: The results suggested that the metabolic interaction should be existed when the substrate drugs of CYP1A2 were co-administered with DCO or traditional Chinese medicine containing it, such as the extract of P. quassioides and Kumu injection.