Inhibitory Effects of Triptolide on Human Liver Cytochrome P450 Enzymes and P-Glycoprotein

Background and Objectives Triptolide is an active component derived from Tripterygium wilfordii and it possesses numerous pharmacological activities. However, it remains unclear how triptolide influences the activity of human liver cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). Methods In this study, the inhibitory effects of triptolide on the 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), and the effects of triptolide on the activity of P-gp were investigated using a rhodamine-123 uptake assay. Results The results showed that triptolide inhibited the activity of CYP1A2 and CYP3A4, with 50 % inhibitory concentration (IC50) values of 14.18 and 8.36 mu M, respectively, but that other CYP isoforms were not affected. Enzyme kinetic studies showed that triptolide was not only a non-competitive inhibitor of CYP1A2, but also a competitive inhibitor of CYP3A4, with inhibition constant (K-i) values of 7.32 and 5.67 mu M, respectively. In addition, triptolide is a time-dependent inhibitor for CYP1A2, and the concentration at 50 % maximum inactivation (K-i) and maximum inactivation (K-inact) values were 286.5 mu M and 0.024 min(-1), respectively. The rhodamine-123 uptake assay showed that triptolide could not affect the activity of P-gp. Conclusions The in vitro studies of triptolide with CYP isoforms and P-gp indicate that triptolide has the potential to cause pharmacokinetic drug interactions with other coadministered drugs metabolized by CYP1A2 and CYP3A4. Further clinical studies are needed to evaluate the significance of this interaction.