药学学报, 2019, 54(6): 1101-1107
引用本文:
尚芳红, 俸珊, 陈乾, 陈先进, 徐晓玉. 加味佛手散胶囊体外体内对大鼠肝脏CYP450酶活性的影响[J]. 药学学报, 2019, 54(6): 1101-1107.
SHANG Fang-hong, FENG Shan, CHEN Qian, CHEN Xian-jin, XU Xiao-yu. Effects of Jiawei Foshou San capsule on rat hepatic cytochrome P450 enzymes in vitro and in vivo[J]. Acta Pharmaceutica Sinica, 2019, 54(6): 1101-1107.

加味佛手散胶囊体外体内对大鼠肝脏CYP450酶活性的影响
尚芳红1, 俸珊2, 陈乾2, 陈先进2, 徐晓玉2
1. 重庆市中药研究院, 重庆 400065;
2. 西南大学药学院中医药学院, 重庆 400715
摘要:
考察加味佛手散胶囊在体外和体内对大鼠肝微粒体CYP1A2、CYP2C6、CYP2D2、CYP2E1、CYP3A1/2亚酶活性的影响,为临床提供药物代谢动力学以及与其他药物合用时的参考。采用肝微粒体体外孵育"鸡尾酒"法,LC-MS/MS法测定代谢产物,评价各受试组CYP同工酶活性,HE染色观察用药前后肝组织病理变化。在体外,最高抑制浓度3 200 mg·L-1加味佛手散胶囊对大鼠肝微粒体CYP2D2、CYP2E1、CYP3A1/2的IC50分别为229.3、361.9和274.6 mg·L-1。在体内,与空白对照组比较,180 mg·kg-1·d-1的加味佛手散胶囊组CYP1A2、CYP2C6和CYP3A1/2的酶活性显著升高(P<0.01)。用药后加味佛手散胶囊组有炎细胞浸润,但病理变化程度明显较延胡索乙素组轻微。体外抑制体内诱导实验提示加味佛手散胶囊临床使用如果与其他经CYP2D2、CYP2E1酶代谢的药物同时使用,可能使该药作用效果增强,作用时间延长,联合用药时应适当减少用药剂量;如果与其他经CYP1A2、CYP2C6酶代谢的药物同时使用,则可能使该药作用效果减弱,作用时间缩短,联合用药时应适当增加用药剂量。另外,延胡索乙素与阿魏酸、川芎嗪联合使用后,能显著降低延胡索乙素对大鼠肝脏的毒性作用。本研究中动物实验方案获得西南大学药学院实验动物管理与使用委员会的批准。
关键词:    加味佛手散胶囊      细胞色素CYP450      延胡索乙素      肝毒性      药物相互作用      药物代谢动力学     
Effects of Jiawei Foshou San capsule on rat hepatic cytochrome P450 enzymes in vitro and in vivo
SHANG Fang-hong1, FENG Shan2, CHEN Qian2, CHEN Xian-jin2, XU Xiao-yu2
1. Chongqing Academy of Chinese Materia Medica, Chongqing 400065, China;
2. College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing 400715, China
Abstract:
This study aimed to evaluate the effects of Jiawei Foshou San capsule (JWFSSC) on CYP1A2, CYP2C6, CYP2D2, CYP2E1 and CYP3A1/2 enzyme activities in rat liver microsomes in vitro and in vivo, and to provide pharmacokinetic data for its combined use with other medicines. After incubating liver microsomes with a cocktail of probe drugs, the metabolites were quantitated with LC-MS/MS to assess the CYP enzyme activity. The hepatic pathological changes were evaluated by histology after hematoxylin and eosin (HE) staining. With the dose range up to 3 200 mg·L-1, the IC50 of JWFSSC for CYP2D2, CYP2E1 and CYP3A1/2 in vitro was 229.3 mg·L-1, 361.9 mg·L-1 and 274.6 mg·L-1 respectively. Compared with the vehicle control group, the enzyme activities of CYP1A2, CYP2C6 and CYP3A1/2 showed a significant increase in animals given JWFSSC 180 mg·kg-1·d-1 (P<0.01). Based on histology, several pathological changes were observed in JWFSSC groups:there was less inflammatory infiltration compared to the tetrahydropalmatine (THP) group. These results of inhibition in vitro and induction in vivo suggest a strengthened efficacy and a prolonged effective time of drugs metabolized by CYP2D2 and CYP2E1 enzymes when combined with JWFSSC in use. The dosage of parent drugs should be appropriately reduced when used in combination with JWFSSC. However, if a drug is metabolized by CYP1A2 and CYP2C6 when used in combination with JWFSSC, the effect of the drug is likely reduced and the dosage should be increased appropriately. In addition, the combination of ferulic acid (FA), ligustrazine (LZ) and THP can significantly reduce the toxicity of THP in rat livers. In this study, the program of animal testing had been approved by Committee on the management and usage of experimental animal in the College of Pharmaceutical Sciences, Southwest University.
Key words:    Jiawei Foshou San capsule    cytochrome P450    tetrahydropalmatine    liver toxicity    drug interaction    pharmacokinetics   
收稿日期: 2019-02-18
DOI: 10.16438/j.0513-4870.2019-0118
基金项目: 科技部重大新药创制专项资助项目(2014ZX09304-306-04);重庆市基础研究与前沿探索项目(cstc2018jcyjAX0669);重庆市科研机构绩效激励引导专项资助项目(cstc2018jxjl-jbky120002).
通讯作者: 徐晓玉
Email: xuxiaoyu@swu.edu.cn
相关功能
PDF(526KB) Free
打印本文
0
作者相关文章
尚芳红  在本刊中的所有文章
俸珊  在本刊中的所有文章
陈乾  在本刊中的所有文章
陈先进  在本刊中的所有文章
徐晓玉  在本刊中的所有文章

参考文献:
[1] Xing HJ, Wang HB, Sun G. Antioxidant response, CYP450 system, and histopathological changes in the liver of nitrobenzene-treated drakes[J]. Res Vet Sci, 2013, 95:1088-1093.
[2] Hu DH, Wang YG, Chen ZW, et al. Effect of compound Danshen Dripping Pills on rat hepatic cytochrome P450[J]. Chin J Pharmacol Toxicol (中国药理学与毒理学杂志), 2013, 27:678-684.
[3] Venkatakrishana K, von Moltke LL, Obach RS, et al. Drug metabolism and drug interactions:application and clinical value of in vitro models[J]. Curr Drug Metab, 2003, 4:423-459.
[4] Bertelsen KM, Venkatakrisnan K, von Moltke LL, et al. Apparent mechanism based inhibition of human CYP2D6 in vitro by paroxetine:comparison with fluoxetine and quinidine[J]. Drug Metab Dispos, 2003, 31:289-293.
[5] Zhu GX, Wang YG, Li F, et al. Study on the effect s of Radix Adenophorae co-administrated with Veratrum nigrum L. on cytochrome P450 subtype enzymes activities of rats by cocktail approach using probe drugs[J]. Chin J Pharmacovigil (中国药物警戒), 2013, 10:257-268.
[6] Xu XY. Pharmacology of Chinese Materia Medica (中药药理学)[M]. Beijing:China Press of Traditional Chinese Medicine, 2010:166-168.
[7] Xu XY, Chen WH, Ye L, et al. Effect of sodium ferulate and total glucosides in paeony on tumor growth and expression of vascular endothelial growth factor and proliferating cell nuclear antigen in H 22 mice[J]. Chin Tradit Herb Drugs (中草药), 2007, 38:570-573.
[8] Tang Q, Shang FH, Wang XC, et al. Combination use of ferulic acid, ligustrazine and tetrahydropalmatine inhibits the growth of ectopic endometrial tissue:a multi-target therapy for endometriosis rats[J]. J Ethnopharmacol, 2014, 151:1218-1225.
[9] Wang J, Yuan Z, Zhao H, et al. Ferulic acid promotes endothelial cells proliferation through up-regulating cyclin D1 and VEGF[J]. J Ethnopharmacol, 2011, 137:992-997.
[10] Yang Y, Wang XC, Chen G, et al. Research of therapeutical effect and immunologic mechanism of Jiawei Foshou San on model rats of endometriosis[J]. China J Chin Mater Med (中国中药杂志), 2011, 36:3001-3006.
[11] He F, Bi HC, Xie ZY, et al. Rapid determination of six metabolites from multiple cytochrome P450 probe substrates in human liver microsome by liquid chromatography/mass spectrometry:application to high-throughput inhibition screening of terpenoids[J]. Rapid Commun Mass Spectrom, 2007, 21:635-643.
[12] Shang FH, Feng S, Chen Q, et al. In vitro inhibitory effects of Jiawei Foshou San capsule on activity of cytochrome P450 enzymes in rat and human liver microsomes[J]. Acta Pharm Sin (药学学报), 2016, 51:926-930.
[13] Yan JJ, He X, Feng S, et al. Up-regulation on cytochromes P450 in rat mediated by total alkaloid extract from Corydalis yanhusuo[J]. BMC Complement Altern Med, 2014, 14:306-314.
[14] Shang FH, Feng S, Zhang FY, et al. Effect of Jiawei Foshou San and its compatibility on hepatic P450 enzyme activity and hepatocyte morphology in rats[J]. China J Chin Mater Med (中国中药杂志), 2015, 40:2030-2036.
[15] Zhong YH, Shen GL, Yuan H, et al. Evaluation of cytochrome P450 inhibition and induction by psoralen and isopsoralen in vitro[J]. Chin J Pharmacol Toxicol (中国药理学与毒理学杂志), 2012, 26:522-528.
[16] Deng J, Shao J, Markowitz JS, et al. ABC transporters in multi-drug resistance and ADME-Tox of small molecule tyrosine kinase inhibitors[J]. Pharm Res, 2014, 31:2237-2255.
[17] Ai CH, Sun HX, Li H, et al. In vitro inhibition of cytochrome P450 activities by active constituents of Chinese herbal drugs[J]. Chin Pharmacol Bull (中国药理学通报), 2011, 27:519-523.
[18] Tan Y, Zhuang XM, Shen GL, et al. Investigation of metabolic kinetics and reaction phenotyping of ligustrazin by using liver microsomes and recombinant human enzymes[J]. Acta Pharm Sin (药学学报), 2014, 49:374-379.
[19] Sun SY, Wang YQ, Li LP, et al. Stereoselective interaction between tetrahydropalmatine enantiomers and CYP enzymes in human liver microsomes[J]. Chirality, 2013, 25:43-47.
[20] Jiang B, Cai F, Gao SH, et al. Induction of cytochrome P4503A by Shexiang Baoxin pill and its main components[J]. Chem Biol Interact, 2012, 195:105-113.
[21] Yan R, Wang Y, Shen WJ, et al. Comparative pharmacokinetics of dehydroevodiamine and coptisine in rat plasma after oral administration of single herbs and Zuojinwan prescription[J]. Fitoterapia, 2011, 82:1152-1159.
[22] Li D, Han YL, Yu T, et al. In vitro inhibition of Huanglianjiedu Decoction on 6 cytochrome P450 isoforms in human liver microsomes[J]. Chin J Chin Pharmacol Ther, 2012, 17:131-136.
[23] Li L, Ye M, Bi K, Guo D. Liquid chromatography-tandem mass spectrometry for the identification of L-tetrahydropalmatine metabolites in Penicillium janthinellum and rats[J]. Biomed Chromatogr, 2006, 20:95-100.
[24] Wang C, Zhou J, Wang S, et al. Shotgun approach based comparative proteomic analysis of levo-tetrahydropalmatine-induced apoptosis in hepatocytes[J]. Toxicol Lett, 2010, 194:8-15.
[25] Chen XY, Huang GH, Ma J, et al. Attaching importance to liver injury caused by Chinese herbal medicine[J]. Chin J Gastroenterol Hepatol (胃肠病学和肝病学杂志), 2008, 7:607-610.
[26] Zhang YL, Cui YQ, Wang XS, et al. Experimental study on effect of Astragalus granules and Astragalus injection on enzymatic activities of CYP1A2, CYP2D and CYP2C[J]. Chin Pharmacol Bull (中国药理学通报), 2013, 29:512-519.
[27] Martignoni M, Groothuis GM, de Kanter R. Species different between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction[J]. Expert Opin Drug Metab Toxicol, 2006, 2:875-894.
相关文献:
1.吴祥猛, 盛莉, 贾雨霏, 李燕.乳腺癌耐药蛋白在药物代谢动力学中的作用[J]. 药学学报, 2016,51(9): 1368-1377
2.尚芳红, 俸珊, 陈乾, 陈先进, 张继芬, 徐晓玉.加味佛手散胶囊对大鼠和人肝微粒体CYP450酶活性的抑制作用[J]. 药学学报, 2016,51(6): 926-930
3.苏成业.P-糖蛋白在药物代谢动力学中的作用及其临床意义[J]. 药学学报, 2005,40(8): 673-679
4.姜玲敏;李雅雅;叶远福;郑太轩;刘萍;高志军.反相高效液相色谱法研究家兔体内利福定对地塞米松代谢动力学的影响[J]. 药学学报, 1988,23(8): 633-635