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

doi:10.1038/aps.2017.170

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	CYP3A4 inducer and inhibitor strongly affect the pharmacokinetics of triptolide and its derivative in rats
	Xu, Ye 1,2; Zhang, Yi-fan2 ; Chen, Xiao-yan1,2 ; Zhong, Da-fang1,2
刊名	ACTA PHARMACOLOGICA SINICA
	2018-08
卷号	39 期号:8 页码:1386-1392
关键词	triptolide (5R)-5-hydroxytriptolide CYP3A4 ritonavir dexamethasone pharmacokinetics immunosuppressant traditional Chinese medicine
ISSN号	1671-4083
DOI	10.1038/aps.2017.170
文献子类	Article
英文摘要	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-infinity) (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-infinity) 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.
资助项目	National Natural Science Foundation of China[81373479] ; National Natural Science Foundation of China[81521005]
WOS关键词	IN-VITRO ; (5R)-5-HYDROXYTRIPTOLIDE LLDT-8 ; TRIPTERYGIUM-WILFORDII ; LIVER-MICROSOMES ; DRUG-METABOLISM ; P-GLYCOPROTEIN ; CYTOCHROME-P450 ; INDUCTION ; TOXICITY ; VIVO
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:6309902
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000441241700013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279635]
专题	上海药物代谢研究中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Zhong, Da-fang
作者单位	1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Xu, Ye,Zhang, Yi-fan,Chen, Xiao-yan,et al. CYP3A4 inducer and inhibitor strongly affect the pharmacokinetics of triptolide and its derivative in rats[J]. ACTA PHARMACOLOGICA SINICA,2018,39(8):1386-1392.
APA	Xu, Ye,Zhang, Yi-fan,Chen, Xiao-yan,&Zhong, Da-fang.(2018).CYP3A4 inducer and inhibitor strongly affect the pharmacokinetics of triptolide and its derivative in rats.ACTA PHARMACOLOGICA SINICA,39(8),1386-1392.
MLA	Xu, Ye,et al."CYP3A4 inducer and inhibitor strongly affect the pharmacokinetics of triptolide and its derivative in rats".ACTA PHARMACOLOGICA SINICA 39.8(2018):1386-1392.