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

Abstract

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 AUC_0-∞ (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 AUC_0-∞ 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: (5R)-5-hydroxytriptolide; CYP3A4; dexamethasone; immunosuppressant; pharmacokinetics; ritonavir; traditional Chinese medicine; triptolide.

Figure 1

Structures of triptolide (A) and (5R)-5-hydroxytriptolide (B).

Figure 2

Enzyme phenotypes of triptolide and (5R)-5-hydroxytriptolide. The incubation system containing triptolide (or (5R)-5-hydroxytriptolide, 3 μmol/L), PBS (100 mmol/L, pH 7.4), CYP450s (50 pmol P450/mL), and NADPH (2 mmol/L) was at a final volume of 100 μL. Each incubation was performed in duplicate. (A) Remaining triptolide. (B) Remaining (5R)-5-hydroxytriptolide. (C) Contribution of CYP450s to the metabolism of triptolide. (D) Contribution of CYP450s to the metabolism of (5R)-5-hydroxytriptolide.

Figure 3

Concentration-time curves of triptolide in rats. Triptolide+ dexamethasone (n=4): rats were orally administered dexamethasone (50 mg/kg, qd) for three consecutive days and then orally administered triptolide (0.4 mg/kg); Triptolide+ritonavir (n=4): rats were orally administered ritonavir (30 mg/kg) 1 h before triptolide (0.4 mg/kg); triptolide only (n=4): rats were orally administered triptolide (0.4 mg/kg) only.

Figure 4

Concentration-time curves of (5R)-5-hydroxytriptolide in rats. (5R)-5-Hydroxytriptolide+dexamethasone (n=4): rats were orally administered dexamethasone (50 mg/kg, qd) for three consecutive days and then were orally administered (5R)-5-hydroxytriptolide (0.4 mg/kg); (5R)-5-Hydroxytriptolide+ritonavir (n=4): rats were orally administered ritonavir (30 mg/kg) 1 h before (5R)-5-hydroxytriptolide (0.4 mg/kg); (5R)-5-Hydroxytriptolide only (n=4): rats were orally administered (5R)-5-hydroxytriptolide (0.4 mg/kg) only.