CYP3A4 inducer and inhibitor strongly affect the pharmacokinetics of triptolide and its derivative in rats
文献类型：期刊论文
| 作者 | Xu, Ye1,2; Zhang, Yi-fan2 ; Chen, Xiao-yan1,2; Zhong, Da-fang1,2
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 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. |
| WOS关键词 | IN-VITRO ; (5R)-5-HYDROXYTRIPTOLIDE LLDT-8 ; TRIPTERYGIUM-WILFORDII ; LIVER-MICROSOMES ; DRUG-METABOLISM ; P-GLYCOPROTEIN ; CYTOCHROME-P450 ; INDUCTION ; TOXICITY ; VIVO |
| 资助项目 | National Natural Science Foundation of China[81373479] ; National Natural Science Foundation of China[81521005] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:6309902 |
| WOS记录号 | WOS:000441241700013 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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