CYP3A4 inducer and inhibitor strongly affect the pharmacokinetics of triptolide and its derivative in rats

Authors: Ye XU1,2, Yi-fan ZHANG1, Xiao-yan CHEN1,2, Da-fang ZHONG1,2
1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
Corresponding to: Da-fang ZHONG:,
DOI: 10.1038/aps.2017.170
Received: 1 August 2017
Accepted: 25 October 2017
Advance online: 28 December 2017


Triptolide is the most active ingredient of Tripterygium wilfordii Hook F, which is used to treat rheumatoid arthritis. (5R)-5- Hydroxytriptolide is a hydroxylation derivative of triptolide with a reduced toxicity. To investigate the metabolic enzymes of the two compounds and the drug-drug interactions with enzyme inducers or inhibitors, a series of in vitro and in vivo experiments were conducted. In vitro studies using recombinant human cytochrome P450 enzyme demonstrated that cytochrome P450 3A4 (CYP3A4) was predominant in the metabolism of triptolide and (5R)-5-hydroxytriptolide, accounting for 94.2% and 64.2% of the metabolism, respectively. Pharmacokinetics studies were conducted in male SD rats following administration of triptolide or (5R)-5-hydroxytriptolide (0.4 mg/kg, po). The plasma exposure to triptolide and (5R)-5-hydroxytriptolide in the rats was significantly increased when co-administered with the CYP3a inhibitor ritonavir (30 mg/kg, po) with the values of AUC0–∞ (area under the plasma concentration-time curve from time zero extrapolated to infinity) being increased by 6.84 and 1.83 times, respectively. When pretreated with the CYP3a inducer dexamethasone (50 mg·kg-1·d-1, for 3 d), the AUC0–∞ values of triptolide and (5R)-5-hydroxytriptolide were decreased by 85.4% and 91.4%, respectively. These results suggest that both triptolide and (5R)-5-hydroxytriptolide are sensitive substrates of CYP3a. Because of their narrow therapeutic windows, clinical drug-drug interaction studies should be carried out to ensure their clinical medication safety and efficacy.
Keywords: triptolide; (5R)-5-hydroxytriptolide; CYP3A4; ritonavir; dexamethasone; pharmacokinetics; immunosuppressant; traditional Chinese medicine