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 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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Lin N, Liu CF, Xiao C, Jia HW, Imada K, Wu H, et al. Triptolide, a diterpenoid triepoxide, suppresses inflammation and cartilage destruction in collagen-induced arthritis mice. Biochem Pharmacol 2007; 73: 136–46.
Panichakul T, Intachote P, Wongkajorsilp A, Sripa B, Sirisinha S. Triptolide sensitizes resistant cholangiocarcinoma cells to TRAIL-induced apoptosis. Anticancer Res 2016; 26: 259–66.
Luo YW, Shi C, Yuan Y, Zhang M, Liao MY. Research progress on the toxicology of triptolide. Dulixue Zazhi 2009; 23: 74–7.
Yang F, Ren L, Zhuo L, Ananda S, Liu L. Involvement of oxidative stress in the mechanism of triptolide-induced acute nephrotoxicity in rats. Exp Toxicol Pathol 2012; 64: 905–11.
Wang JY, Jiang ZZ, Ji JZ, Wang XZ, Wang T, Zhang Y, et al. Gene expression profiling and pathway analysis of hepatotoxicity induced by triptolide in Wistar rats. Food Chem Toxicol 2013; 58: 495–505.
Zhou R, Zhang F, He PL, Zhou WL, Wu QL, Xu JY, et al. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide analog mediates immunosuppressive effects in vitro and in vivo. Int Immunopharmacol 2005; 5: 1895–903.
Tang W, Zuo JP. Immunosuppressant discovery from Tripterygium wilfordii Hook F: the novel triptolide analog (5R)-5-hydroxytriptolide (LLDT-8). Acta Pharmacol Sin 2012; 33: 1112–8.
Liu J, Li L, Zhou X, Chen XY, Huang HH, Zhao SB, et al. Metabolite profiling and identification of triptolide in rats. J Chromatogr B Analyt Technol Biomed Life Sci 2013; 939: 51–8.
Liu J, Zhou X, Chen XY, Zhong DF. Excretion of [3H]triptolide and its metabolites in rats after oral administration. Acta Pharmacol Sin 2014; 35: 549–54.
Li W, Liu Y, He YQ, Zhang JW, Gao Y, Ge GB, et al. Characterization of triptolide hydroxylation by cytochrome P450 in human and rat liver microsomes. Xenobiotica 2008; 38: 1551–65.
Tai T, Huang X, Su YW, Ji J, Su YJ, Jiang ZZ, et al. Glycyrrhizin accelerates the metabolism of triptolide through induction of CYP3A in rats. J Ethnopharmacol 2014; 152: 358–63.
Xue X, Gong LK, Qi XM, Wu YF, Xing GZ, Yao J, et al. Knockout of hepatic P450 reductase aggravates triptolide-induced toxicity. Toxicol Lett 2011; 205: 47–54.
Ye XC, Li WY, Yan Y, Mao CW, Cai RX, Xu HB, et al. Effects of cytochrome P4503A inducer dexamethasone on the metabolism and toxicity of triptolide in rat. Toxicol Lett 2010; 192: 212–20.
Kumar S, Kwei GY, Poon GK, Iliff SA, Wang YF, Chen Q, et al. Pharmacokinetics and interactions of a novel antagonist of chemokine receptor 5 (CCR5) with ritonavir in rats and monkeys: Role of CYP3A and P-glycoprotein. J Pharmacol Exp Ther 2003; 304: 1161–71.
Liu J, Chen XY, Zhang YF, Miao H, Liu K, Li L, et al. Derivatization of (5R)-hydroxytriptolide from benzylamine to enhance mass spectrometric detection: application to a Phase I pharmacokinetic study in humans. Anal Chim Acta 2011; 689: 69–76.
Zhao SB, Huang HH, Chen XY, Li XL, Zhong DF. Biotransformation of triptolide to (5R)-hydroxytriptolide. Zhongguo Xinyao Zazhi 2012; 21: 7.
Rodrigues AD. Integrated cytochrome P450 reaction phenotyping: attempting to bridge the gap between cDNA-expressed cytochromes P450 and native human liver microsomes. Biochem Pharmacol 1999; 57: 465–80.
Martignoni M, Groothuis GM, de Kanter R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol 2006; 2: 875–94.
Bogaards JJ, Bertrand M, Jackson P, Oudshoorn MJ, Weaver RJ, van Bladeren PJ, et al. Determining the best animal model for human cytochrome P450 activities: a comparison of mouse, rat, rabbit, dog, micropig, monkey and man. Xenobiotica 2000; 30: 1131–52.
Zuber R, Anzenbacherova E, Anzenbacher P. Cytochromes P450 and experimental models of drug metabolism. J Cell Mol Med 2002; 6: 189–98.
Lu C, Li AP. Species comparison in P450 induction: effects of dexamethasone, omeprazole, and rifampin on P450 isoforms 1A and 3A in primary cultured hepatocytes from man, Sprague-Dawley rat, minipig, and beagle dog. Chem-Biol Interact 2001; 134: 271–81.
Meredith C, Scott MP, Renwick AB, Price RJ, Lake BG. Studies on the induction of rat hepatic CYP1A, CYP2B, CYP3A and CYP4A subfamily form mRNAs in vivo and in vitro using precision-cut rat liver slices. Xenobiotica 2003; 33: 511–27.
European medicines agency (Europe). Guideline on the investigation of drug interactions. London: Committee for human medicinal products; 2012.
Food and administration (US). Services. Guidance for industry: drug interaction studies — study design, data analysis, implications for dosing, and labeling recommendations. Washington: Center for drug evaluation and research; 2012.
Zhuang XM, Shen GL, Xiao WB, Tan Y, Lu C, Li H. Assessment of the roles of P-glycoprotein and cytochrome P450 in triptolide-induced liver toxicity in sandwich-cultured rat hepatocyte model. Drug Metab Dispos 2013; 41: 2158–65.
Du FY, Liu ZH, Li XX, Xing J. Metabolic pathways leading to detoxification of triptolide, a major active component of the herbal medicine Tripterygium wilfordii. J Appl Toxicol 2014; 34: 878–84.
Vermeer LM, Isringhausen CD, Ogilvie BW, Buckley DB. Evaluation of ketoconazole and its alternative clinical CYP3A4/5 inhibitors as inhibitors of drug transporters: the in vitro effects of ketoconazole, ritonavir, clarithromycin, and itraconazole on 13 clinically-relevant drug transporters. Drug Metab Dispos 2016; 44: 453–9.
Li CZ, Xing GZ, Maeda K, Wu CY, Gong LK, Sugiyama Y, et al. The role of breast cancer resistance protein (Bcrp/Abcg2) in triptolide-induced testis toxicity. Toxicol Res 2015; 4: 1260–8.
Jia Y, Liu Z, Wang C, Meng Q, Huo X, Liu Q, et al. P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between resveratrol and methotrexate. Toxicol Appl Pharmacol 2016; 306: 27–35.
Wang L, Wang C, Peng J, Liu Q, Meng Q, Sun H, et al. Dioscin enhances methotrexate absorption by down-regulating MDR1 in vitro and in vivo. Toxicol Appl Pharmacol 2014; 277: 146–54.
Rengelshausen J, Goggelmann C, Burhenne J, Riedel KD, Ludwig J, Weiss J, et al. Contribution of increased oral bioavailability and reduced nonglomerular renal clearance of digoxin to the digoxin-clarithromycin interaction. Brit J Clin Pharmaco 2003; 56: 32–8.
Zhang YC, Li J, Lei XL, Zhang TY, Liu GX, Yang MH, et al. Influence of verapamil on pharmacokinetics of triptolide in rats. Eur J Drug Metab Pharmacokinet 2016; 41: 449–56.
Acknowledgements
This study was supported by the National Natural Science Foundation of China (No 81373479 and 81521005). The authors thank the Investment and Development Department of Shanghai Pharmaceuticals Holding Co, Ltd (Shanghai, China) for providing the standard reference of (5R)-5-hydroxytriptolide; Jia-lan ZHOU and Yun-ting ZHU for their assistance with the enzyme experiments; and Ying YANG, Si-wen SUN, and Guang-ying SHEN for their help with the animal experiments.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Xu, Y., Zhang, Yf., Chen, Xy. et al. CYP3A4 inducer and inhibitor strongly affect the pharmacokinetics of triptolide and its derivative in rats. Acta Pharmacol Sin 39, 1386–1392 (2018). https://doi.org/10.1038/aps.2017.170
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2017.170
Keywords
This article is cited by
-
Metabolic characterization of a potent natural neuroprotective agent dendrobine in vitro and in rats
Acta Pharmacologica Sinica (2022)
