药学学报, 2021, 56(1): 274-282
引用本文:
姜波, 石美智, 陈君君, 杨姣, 张科之, 郭澄, 韩永龙. 体外系统性评价79种中药注射剂对9种人细胞色素P450酶的抑制作用[J]. 药学学报, 2021, 56(1): 274-282.
JIANG Bo, SHI Mei-zhi, CHEN Jun-jun, YANG Jiao, ZHANG Ke-zhi, GUO Cheng, HAN Yong-long. In vitro inhibition by 79 herb injectables of nine human cytochrome P450 isoenzymes: a systematic evaluation of herb-drug interactions[J]. Acta Pharmaceutica Sinica, 2021, 56(1): 274-282.

体外系统性评价79种中药注射剂对9种人细胞色素P450酶的抑制作用
姜波1, 石美智1, 陈君君1, 杨姣1, 张科之2, 郭澄1, 韩永龙1
1. 上海交通大学附属第六人民医院药剂科, 上海 200233;
2. 科志康医药科技有限公司, 广东 佛山 528000
摘要:
中药注射剂在临床经常与化学药物联用治疗多种复杂疾病,但其中药-药物的相互作用还没有得到充分的研究,有时甚至被临床忽视。本文研究国家食品药品监督管理局批准的79种中药注射剂,评价它们对人体药物代谢酶-细胞色素P450(CYP450)的潜在抑制作用。使用9种人CYP450s(包括CYP1A、CYP2A6、CYP2B6、CYP2C8、CYP2C9、CYP2C19、CYP2D6、CYP2E1和CYP3A)、特异性底物和中药注射剂共同孵育,使用灵敏度、准确度高的液相串联质谱(LC-MS/MS)对探针形成的代谢产物进行定量分析,评价79种中药注射剂对CYP450的体外抑制作用。在79种中药注射液中,当在中药注射液5%(v/v)和注射用粉针剂2倍日最大使用剂量换算浓度CMDD(mg·mL-1)筛选时有37种中药注射剂对CYP1A、24种中药注射剂对CYP2A6、41种中药注射剂对CYP2B6、36种中药注射剂对CYP2C9、41种中药注射剂对CYP2C19、41种中药注射剂对CYP2D6、25种中药注射剂对CYP2E1和42种中药注射剂对CYP3A表现出50%的抑制率或更强的抑制作用。在预孵育或与人肝微粒体共孵育30 min后,观察到2种中药注射剂对CYP1A、5种中药注射剂对CYP2A6、5种中药注射剂对CYP2B6、6种中药注射剂对CYP2C8、1种中药注射剂对CYP2D6、6种中药注射剂对CYP3A呈现时间依赖性抑制(TDI)作用。结果表明,中药注射剂存在基于CYP450的中药-药物相互作用及时间依赖性的中药-药物相互作用,需要临床医生用药提高警惕。
关键词:    中药注射剂      细胞色素P450      抑制作用      中药-药物相互作用     
In vitro inhibition by 79 herb injectables of nine human cytochrome P450 isoenzymes: a systematic evaluation of herb-drug interactions
JIANG Bo1, SHI Mei-zhi1, CHEN Jun-jun1, YANG Jiao1, ZHANG Ke-zhi2, GUO Cheng1, HAN Yong-long1
1. Department of Pharmacy, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China;
2. KG Pharma Limited, Foshan 528000, China
Abstract:
Seventy-nine injectable herb extractions have been approved by the Chinese Food and Drug Administration (CFDA) and are frequently administered intravenously for various diseases. Unfortunately, herb-drug interactions are under-investigated and sometimes overlooked in the clinic. In the present investigation the in vitro inhibition of 9 drug metabolizing enzymes including CYP1A, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A was assessed using an appropriate probe substrate for each enzyme with human liver microsomes. Metabolite formation was quantified using a validated and sensitive high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. The IC50 of each herb extract was estimated using a concentration range from 5% to 0.5%, and the time-dependent inhibition of the nine CYP450 isoenzymes was also determined. Of the 79 approved iv herb injectables, 37 inhibited CYP1A, 24 inhibited CYP2A6, 41 inhibited CYP2B6, 36 inhibited CYP2C8, 31 inhibited CYP2C9, 41 inhibited CYP2C19, 13 inhibited CYP2D6, 25 inhibited CYP2E1, and 42 inhibited CYP3A with 50% or greater inhibition at a test concentration of 5% (v/v). IC50 differences were noted between pre-incubation or co-incubation assays with HLM for 30 min, with the time-dependent inhibitory (TDI) effects were observed with 2 injectables on CYP1A, 5 injectables on CYP2A6, 5 injectables on CYP2B6, 6 injectables on CYP2C8, 1 injectable on CYP2D6 and 6 injectables on CYP3A. Collectively, the results demonstrate that potential herb-drug interactions (HDIs) can occur with the concomitant use of herb injectables and prescription drugs that are cleared by CYP450 enzymes, and further investigation is warrant for the clinical relevance of these interactions.
Key words:    herb extract injectables    cytochrome P450    inhibition    herb-drug interaction   
收稿日期: 2020-08-15
DOI: 10.16438/j.0513-4870.2020-1338
基金项目: 国家自然科学基金面上项目(81773949);上海市浦东新区科技发展基金民生科研专项资金医疗卫生项目(PKJ2017-Y07、PKJ2019-Y04);上海市浦东新区卫生和计划生育委员会科研项目(PW2017E-2);上海市卫生和计划生育委员会科研项目(20174Y0023);上海健康医学院师资人才百人库项目(B3-0200-20-311008-02).
通讯作者: 郭澄,Tel:86-21-24058098,E-mail:guopharm@126.com;韩永龙,Tel:86-21-38297199,E-mail:yonglongh@126.com
Email: guopharm@126.com;yonglongh@126.com
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参考文献:
[1] Li X, Chen H, Jia W, et al. A metabolomics-based strategy for the quality control of traditional Chinese medicine:shengmai injection as a case study[J]. Evid Based Complement Alternat Med, 2013, 2013:836179.
[2] Xu HM, Wang Y, Liu NF. Safety of an injection with a mixture of extracts from Herba Artemisiae Annuae, Fructus Gardeniae and Flos Lonicerae[J]. Pharm World Sci, 2009, 31:458-463.
[3] Liu LY. In vitro inhibition of 4 anti-tumor traditional Chinese medicine injections on activities of 7 main cytochrome P450s in human liver microsome[J].Chin J Clin Pharm Ther (中国临床药理学与治疗学), 2014, 19:522-527.
[4] Zou L. Advanced in drug-drug interactions among traditional Chinese medicine injections[J]. Cent South Pharm (中南药学), 2016, 14:1183-1187.
[5] Han YL, Li D, Ren B, et al. Evaluation of impact of Herba Erigerontis injection, a Chinese herbal prescription, on rat hepatic cytochrome P450 enzymes by cocktail probe drugs[J]. J Ethnopharmacol, 2012, 139:104-109.
[6] Ye LH, Zhao XQ, Kong LT, et al. Inhibitory effects of Danhong Injection and its major constituents on human cytochrome P450 enzymes in vitro [J]. Biomed Chromatogr, 2018, 32:e4250.
[7] Chatterjee P, Franklin MR. Human cytochrome p450 inhibition and metabolic-intermediate complex formation by goldenseal extract and its methylenedioxyphenyl components[J]. Drug Metab Dispos, 2003, 31:1391-1397.
[8] Walsky RL, Gaman EA, Obach RS. Examination of 209 drugs for inhibition of cytochrome P4502C8[J]. J Clin Pharmacol, 2005, 45:68-78.
[9] Zhang F, Huang J, He RJ, et al. Herb-drug interaction between Styrax and warfarin:molecular basis and mechanism[J]. Phytomedicine, 2020, 77:153287.
[10] Gao XY, Guo MX, Li Q, et al. Plasma metabolomic profiling to reveal antipyretic mechanism of Shuang-huang-lian injection on yeast-induced pyrexia rats[J]. PLoS One, 2014, 9:e100017.
[11] Tian J. Determination of matrine, sophoridine and oxymatrine in Compound Kushen Injection by HPLC[J]. China J Chin Mater Med (中国中药杂志), 2007, 32:222-224.
[12] Ge GB. Deciphering the metabolic fates of herbal constituents and the interactions of herbs with human metabolic system[J]. Chin J Nat Med, 2019, 17:801-802.
[13] Hei H, Zhang Y, Xu DQ, et al. Metabolism of the synthetic cannabinoid PX-2 inhuman liver microsomes[J]. Acta Pharm Sin (药学学报), 2020, 55:1201-1208.
[14] Shang FH, Feng S, Chen Q, et al. Effects of Jiawei Foshou San capsule on rat hepatic cytochrome P450 enzymes in vitro and in vivo[J]. Acta Pharm Sin (药学学报), 2019, 54:1101-1107.
[15] Zhang JX, Qi MJ, Shi MZ, et al. Effects of Danhong injection, a traditional Chinese medicine, on nine cytochrome P450 isoforms in vitro[J]. Biomed Chromatogr, 2019, 33:e4454.
[16] Li Z, Hou J, Li W, et al. Effect of injection of Yiqi Fumai Lyophilized Injection on activity of CYP450 subtypes in human live[J]. Drug Eval Res (药物评价研究), 2018, 41:1224-1228.
[17] Han YL, Dan L, Bin R, et al. Evaluation of impact of Herba Erigerontis injection, a Chinese herbal prescription, on rat hepatic cytochrome P450 enzymes by cocktail probe drugs[J]. J Ethnopharmacol, 2012, 139:104-109.
[18] Xie SS, Wang P, Guo JJ, et al. Research advances of time-dependent inhibition of cytochrome P450 enzymes in drug discovery and development[J]. Chin J New Drugs Clin Rem (中国新药与临床杂志), 2013, 32:419-426.
[19] Zhou QH, Zhu YD, Zhang F, et al. Interactions of drug-metabolizing enzymes with the Chinese herb Psoraleae Fructus[J]. Chin J Nat Med, 2019, 17:858-870.