In vitro inhibitory effects of cepharanthine on human liver cytochrome P450 enzymes

CONTEXT: Cepharanthine (CEP) extracted from the roots of Stephania cepharantha Hayata (Menispermaceae), has a range of therapeutic potential in clinical conditions. Whether it affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. MATERIALS AND METHODS: The effects of CEP (100 μM) on eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) were investigated in vitro using human liver microsomes (HLMs) with specific probe actions and probe substrates. In addition, the enzyme kinetic parameters were calculated. RESULTS: The results showed that the activity of CYP3A4, CYP2E1 and CYP2C9 was inhibited by CEP, with IC(50) values of 16.29, 25.62 and 24.57 μM, respectively, but other CYP isoforms were not affected. Enzyme kinetic studies showed that CEP was not only a non-competitive inhibitor of CYP3A4 but also a competitive inhibitor of CYP2E1 and CYP2C9, with Ki values of 8.12, 11.78 and 13.06 μM, respectively. Additionally, CEP is a time-dependent inhibitor for CYP3A4 with K(I)/K(inact) value of 10.84/0.058 min/μM. DISCUSSION AND CONCLUSIONS: The in vitro studies of CEP with CYP isoforms indicate that CEP has the potential to cause pharmacokinetic drug interactions with other co-administered drugs metabolized by CYP3A4, CYP2E1 and CYP2C9. Further clinical studies are needed to evaluate the significance of this interaction.