药学学报, 2022, 57(5): 1263-1272
周剑雄, 吴送姑, 龚俊波, 魏振平*. 小檗碱的药理活性以及提升其口服生物利用度的策略[J]. 药学学报, 2022, 57(5): 1263-1272.
ZHOU Jian-xiong, WU Song-gu, GONG Jun-bo, WEI Zhen-ping*. Pharmacological activities of berberine and strategies to improve its oral bioavailability[J]. Acta Pharmaceutica Sinica, 2022, 57(5): 1263-1272.

周剑雄, 吴送姑, 龚俊波, 魏振平*
天津大学化工学院, 天津 300350
小檗碱(berberine)是一种天然存在的苄基异喹啉类生物碱,具有抗菌、抗癌、降血脂、抗糖尿病和止泻等广泛药理活性,但因其极低的口服生物利用度(<1%),限制了其在临床上的应用,尚无纯小檗碱配方被批准用于任何特定疾病。小檗碱口服生物利用度低主要是由于其在酸性条件下自聚集导致的溶解度差、渗透性低、P-gp (P-glycoprotein)介导的外排和肝肠代谢。提高小檗碱的口服生物利用度可提高小檗碱的药理活性,降低给药剂量进而减少不良反应。本文综述了小檗碱的多种药理活性、代谢过程、药代动力学特征,重点介绍了通过提高溶解度和渗透性、抑制P-gp外排和结构修饰等途径提高小檗碱口服生物利用度的策略,并对小檗碱的研究进行了展望,为其深入研究提供指导。
关键词:    小檗碱      药理活性      药物代谢      药代动力学      口服生物利用度     
Pharmacological activities of berberine and strategies to improve its oral bioavailability
ZHOU Jian-xiong, WU Song-gu, GONG Jun-bo, WEI Zhen-ping*
School of Chemical Engineering, Tianjin University, Tianjin 300350, China
Berberine is a naturally occurring benzylisoquinoline alkaloid with a wide range of pharmacological activities, such as antibacterial, anticancer, hypolipidemic, antidiabetic and antidiarrheal. Although berberine has a wide range of curative effects, the extremely low bioavailability (< 1%) limits its clinical application. Pure berberine preparations have not yet been approved for any specific disease. The low oral bioavailability of berberine is mainly due to poor solubility caused by self-aggregation under acidic conditions, low permeability, P-glycoprotein (P-gp)-mediated efflux, and liver and intestine metabolism. To improve the oral bioavailability of berberine, researchers have adopted a variety of strategies, including the application of various nano-delivery systems, penetration enhancers and P-gp inhibitors, structural modifications, and development of berberine derivatives. Improving the oral bioavailability of berberine can improve the pharmacological activity of berberine, reduce the dosage, and then reduce the toxic and side effects. This review summarized the various pharmacological activities, metabolism progress and pharmacokinetic characteristics of berberine, the newly discovered berberine target intestinal microbiota and focused on the strategies to improve the oral bioavailability of berberine by improving solubility and permeability, inhibiting P-gp efflux, and structural modification. The research on berberine was prospected, which provided guidance for the in-depth study of berberine.
Key words:    berberine    pharmacological activity    drug metabolism    pharmacokinetics    oral bioavailability   
收稿日期: 2021-09-06
DOI: 10.16438/j.0513-4870.2021-1302
基金项目: 国家自然科学基金资助项目(22078234,22178254).
通讯作者: 魏振平,Tel:13752416756,E-mail:zpwei2000@sina.com
Email: zpwei2000@sina.com
PDF(547KB) Free
周剑雄  在本刊中的所有文章
吴送姑  在本刊中的所有文章
龚俊波  在本刊中的所有文章
魏振平*  在本刊中的所有文章

[1] Chen L, Zhu L, Chen JL, et al. Crystal structure-guided design of berberine-based novel chitinase inhibitors[J]. J Enzyme Inhib Med Chem, 2020, 35:1937-1943.
[2] Parth P. A bird's eye view on a therapeutically ‘wonder molecule’:berberine[J]. Phytomedicine Plus, 2021, 1:100070.
[3] Rabbani GH, Butler T, Knight J, et al. Randomized controlled trial of berberine sulfate therapy for diarrhea due to enterotoxigenic Escherichia coli and Vibrio cholerae[J]. J Infect Dis, 1987, 155:979-984.
[4] Di Pierro F, Bertuccioli A, Giuberti R, et al. Role of a berberine-based nutritional supplement in reducing diarrhea in subjects with functional gastrointestinal disorders[J]. Minerva Gastroenterol Dietol, 2020, 66:29-34.
[5] Yu M, Jin X, Liang C, et al. Berberine for diarrhea in children and adults:a systematic review and meta-analysis[J]. Ther Adv Gastroenterol, 2020, 13:1756284820961299.
[6] Dubreuil JD. Antibacterial and antidiarrheal activities of plant products against enterotoxinogenic Escherichia coli[J]. Toxins, 2013, 5:2009-2041.
[7] Raju M, Kulkarni YA, Wairkar S. Therapeutic potential and recent delivery systems of berberine:a wonder molecule[J]. J Funct Foods, 2019, 61:103517.
[8] Zhang XM, Yang YS, Gang S, et al. Berberine-, allicin-or clarithromycin-based triple therapy for the first-line treatment of Helicobacter pylori infection:an open-label, randomized trial[J]. Gastroenterology, 2014, 146:S398.
[9] Lin Y, Si SY, Jiang JD. Antibacterial activity of berberine[J]. Acta Pharm Sin (药学学报), 2018, 53:163-168.
[10] Du GF, Le YJ, Sun X, et al. Proteomic investigation into the action mechanism of berberine against Streptococcus pyogenes[J]. J Proteomics, 2020, 215:103666.
[11] Gupta S, Gupta R, Gupta J. Evaluation of pharmacodynamic interaction between berberine and antibacterial drug (azithromycin) in albino Wistar rats[J]. Curr Trends Biotechnol Pharm, 2021, 15:256-267.
[12] Zhou J, Pan J, Xiang Z, et al. Xiaokeyinshui extract combination, a berberine-containing agent, exerts anti-diabetic and renal protective effects on rats in multi-target mechanisms[J]. J Ethnopharmacol, 2020, 262:113098.
[13] Feng X, Sureda A, Jafari S, et al. Berberine in cardiovascular and metabolic diseases:from mechanisms to therapeutics[J]. Theranostics, 2019, 9:1923-1951.
[14] Di S, Han L, An X, et al. In silico network pharmacology and in vivo analysis of berberine-related mechanisms against type 2 diabetes mellitus and its complications[J]. J Ethnopharmacol, 2021, 276:114180.
[15] Kong W, Wei J, Abidi P, et al. Berberine is a promising novel cholesterol-lowering drug working through a unique mechanism distinct from statins[J]. Nat Med, 2004, 10:1344-1351.
[16] Li DD, Yu P, Xiao W, et al. Berberine:a promising natural isoquinoline alkaloid for the development of hypolipidemic drugs[J]. Curr Top Med Chem, 2020, 20:2634-2647.
[17] Gonnelli S, Caffarelli C, Stolakis K, et al. Efficacy and tolerability of a nutraceutical combination (red yeast rice, policosanols, and berberine) in patients with low-moderate risk hypercholesterolemia:a double-blind, placebo-controlled study[J]. Curr Ther Res Clin Exp, 2015, 77:1-6.
[18] Li G, Zhao M, Qiu F, et al. Pharmacokinetic interactions and tolerability of berberine chloride with simvastatin and fenofibrate:an open-label, randomized, parallel study in healthy Chinese subjects[J]. Drug Des, Dev Ther, 2019, 13:129-139.
[19] Natalia BM, Gabriela CS, Juan CRB, et al. Natural compounds as modulators of cell cycle arrest:application for anticancer chemotherapies[J]. Curr Genomics, 2017, 18:106-131.
[20] Habtemariam S. Recent advances in berberine inspired anticancer approaches:from drug combination to novel formulation technology and derivatization[J]. Molecules, 2020, 25:1426-1456.
[21] Liu B, Wang GS, Yang J, et al. Berberine inhibits human hepatoma cell invasion without cytotoxicity in healthy hepatocytes[J]. PLoS One, 2011, 6:e21416.
[22] Wang LH, Liu LP, Shi Y, et al. Berberine induces caspase-independent cell death in colon tumor cells through activation of apoptosis-inducing factor[J]. PLoS One, 2012, 7:e36468.
[23] Samadi P, Sarvarian P, Gholipour E, et al. Berberine:a novel therapeutic strategy for cancer[J]. IUBMB Life, 2020, 72:2065-2079.
[24] Park SH, Sung JH, Kim EJ, et al. Berberine induces apoptosis via ROS generation in PANC-1 and MIA-PaCa2 pancreatic cell lines[J]. Braz J Med Biol Res, 2015, 48:111-119.
[25] Spinozzi S, Colliva C, Camborata C, et al. Berberine and its metabolites:relationship between physicochemical properties and plasma levels after administration to human subjects[J]. J Nat Prod, 2014, 77:766-772.
[26] Liao Z, Xie Y, Zhou B, et al. Berberine ameliorates colonic damage accompanied with the modulation of dysfunctional bacteria and functions in ulcerative colitis rats[J]. Appl Microbiol Biotechnol, 2020, 104:1737-1749.
[27] Xu X, Gao Z, Yang F, et al. Antidiabetic effects of Gegen Qinlian Decoction via the gut microbiota are attributable to its key ingredient berberine[J]. Genomics, Proteomics Bioinf, 2020, 18:721-736.
[28] Shi YF, Hu JX, Geng J, et al. Berberine treatment reduces atherosclerosis by mediating gut microbiota in apoE-/- mice[J]. Biomed Pharmacother, 2018, 107:1556-1563.
[29] Pan HJ, Li ZF, Xie J, et al. Berberine influences blood glucose via modulating the gut microbiome in grass carp[J]. Front Microbiol, 2019, 10:1066.
[30] Cui HX, Hu YN, Li JW, et al. Hypoglycemic mechanism of the berberine organic acid salt under the synergistic effect of intestinal flora and oxidative stress[J]. Oxid Med Cell Longevity, 2018, 2018:8930374.
[31] Yang S, Li D, Yu Z, et al. Multi-pharmacology of berberine in atherosclerosis and metabolic diseases:potential contribution of gut microbiota[J]. Front Pharmacol, 2021, 12:709629.
[32] Liu YT, Hao HP, Xie HG, et al. Extensive intestinal first-pass elimination and predominant hepatic distribution of berberine explain its low plasma levels in rats[J]. Drug Metab Dispos, 2010, 38:1779-1784.
[33] Chen W, Miao YQ, Fan DJ, et al. Bioavailability study of berberine and the enhancing effects of TPGS on intestinal absorption in rats[J]. AAPS Pharmscitech, 2011, 12:705-711.
[34] Tan XS, Ma JY, Feng R, et al. Tissue distribution of berberine and its metabolites after oral administration in rats[J]. PLoS One, 2013, 8:e77969
[35] Chen J, Zhang Yl, Dong Y, et al. Enzyme reaction kinetics, metabolic enzyme phenotype, and metabolites of berberine[J]. Chin Tradit Herb Drugs (中草药), 2013, 44:3334-3340.
[36] Ma JY, Feng R, Tan XS, et al. Excretion of berberine and its metabolites in oral administration in rats[J]. J Pharm Sci, 2013, 102:4181-4192.
[37] Wang GH, Wang JY, Huang J, et al. Solid dispersion of berberine hydrochloride and Eudragit S100:formulation and physicochemical characterization[J]. J Shenyang Pharm Univ (沈阳药科大学学报), 2019, 36:1-6.
[38] Gao J, Fan D, Song P, et al. Preparation and application of pH-responsive composite hydrogel beads as potential delivery carrier candidates for controlled release of berberine hydrochloride[J]. R Soc Open Sci, 2020, 7:200676.
[39] Marino M, Gardana C, Scialpi A, et al. An in vitro approach to study the absorption of a new oral formulation of berberine[J]. PharmaNutrition, 2021, 18:100279.
[40] Zhu JX, Tang D, Feng L, et al. Development of self-microemulsifying drug delivery system for oral bioavailability enhancement of berberine hydrochloride[J]. Drug Dev Ind Pharm, 2013, 39:499-506.
[41] Pund S, Borade G, Rasve G. Improvement of anti-inflammatory and anti-angiogenic activity of berberine by novel rapid dissolving nanoemulsifying technique[J]. Phytomedicine, 2014, 21:307-314.
[42] Meng ZJ, Zhang M, Wei SN, et al. Amorphous solid dispersion of berberine with absorption enhancer demonstrates a remarkable hypoglycemic effect via improving its bioavailability[J]. Int J Pharm, 2014, 467:50-59.
[43] Mishra R, Dhole S. Lipid-based floating multiparticulate delivery system for bioavailability enhancement of berberine hydrochloride[J]. J Appl Pharm Sci, 2019, 9:36-47.
[44] Sahibzada MUK, Sadiq A, Faidah HS, et al. Berberine nanoparticles with enhanced in vitro bioavailability:characterization and antimicrobial activity[J]. Drug Des Devel Ther, 2018, 12:303-312.
[45] Sahibzada MUK, Zahoor M, Sadiq A, et al. Bioavailability and hepatoprotection enhancement of berberine and its nanoparticles prepared by liquid antisolvent method[J]. Saudi J Biol Sci, 2021, 28:327-332.
[46] Wang ZP, Wu JB, Zhou Q, et al. Berberine nanosuspension enhances hypoglycemic efficacy on streptozotocin induced diabetic C57BL/6 mice[J]. Evid Based Complement Alternat Med, 2015, 2015:239749.
[47] Shen R, Kim JJ, Yao M, et al. Development and evaluation of vitamin E D-‍α‍-tocopheryl polyethylene glycol 1000 succinate-mixed polymeric phospholipid micelles of berberine as an anticancer nanopharmaceutical[J]. Int J Nanomed, 2016, 11:1687-1700.
[48] Kwon M, Lim DY, Lee CH, et al. Enhanced intestinal absorption and pharmacokinetic modulation of berberine and its metabolites through the inhibition of P-glycoprotein and intestinal metabolism in rats using a berberine mixed micelle formulation[J]. Pharmaceutics, 2020, 12:882.
[49] Gupta L, Sharma AK, Gothwal A, et al. Dendrimer encapsulated and conjugated delivery of berberine:a novel approach mitigating toxicity and improving in vivo pharmacokinetics[J]. Int J Pharm, 2017, 528:88-99.
[50] Wang A, Yang W, Yang X, et al. MgAl monolayer hydrotalcite increases the hypoglycemic effect of berberine by enhancing its oral bioavailability[J]. Biomed Pharmacother, 2020, 127:110140.
[51] Liu CS, Zheng YR, Zhang YF, et al. Research progress on berberine with a special focus on its oral bioavailability[J]. Fitoterapia, 2016, 109:274-282.
[52] Zhang M, Lv XY, Li J, et al. Sodium caprate augments the hypoglycemic effect of berberine via AMPK in inhibiting hepatic gluconeogenesis[J]. Mol Cell Endocrinol, 2012, 363:122-130.
[53] Lv XY, Li J, Zhang M, et al. Enhancement of sodium caprate on intestine absorption and antidiabetic action of berberine[J]. AAPS PharmSciTech, 2010, 11:372-382.
[54] Chen W, Fan DJ, Meng LK, et al. Enhancing effects of chitosan and chitosan hydrochloride on intestinal absorption of berberine in rats[J]. Drug Dev Ind Pharm, 2012, 38:104-110.
[55] Godugu C, Patel AR, Doddapaneni R, et al. Approaches to improve the oral bioavailability and effects of novel anticancer drugs berberine and betulinic acid[J]. PLoS One, 2014, 9:e89919.
[56] Narade S, Pore Y. Optimization of ex vivo permeability characteristics of berberine in presence of quercetin using 32 full factorial design[J]. J Appl Pharm Sci, 2019, 9:73-82.
[57] Shi CY, Tong Q, Fang JG, et al. Preparation, characterization and in vivo studies of amorphous solid dispersion of berberine with hydrogenated phosphatidylcholine[J]. Eur J Pharm Sci, 2015, 74:11-17.
[58] Li YJ, Hu XB, Lu XL, et al. Nanoemulsion-based delivery system for enhanced oral bioavailability and Caco-2 cell monolayers permeability of berberine hydrochloride[J]. Drug Deliv, 2017, 24:1868-1873.
[59] Xu HY, Liu CS, Huang CL, et al. Nanoemulsion improves hypoglycemic efficacy of berberine by overcoming its gastrointestinal challenge[J]. Colloids Surf B Biointerfaces, 2019, 181:927-934.
[60] Li J, Yang L, Shen R, et al. Self-nanoemulsifying system improves oral absorption and enhances anti-acute myeloid leukemia activity of berberine[J]. J Nanobiotechnol, 2018, 16:76-88.
[61] Yin JT, Hou YT, Yin YY, et al. Selenium-coated nanostructured lipid carriers used for oral delivery of berberine to accomplish a synergic hypoglycemic effect[J]. Int J Nanomed, 2017, 12:8671-8680.
[62] Jia JF, Zhang KR, Zhou X, et al. Berberine-loaded solid proliposomes prepared using solution enhanced dispersion by supercritical CO2:sustained release and bioavailability enhancement[J]. J Drug Delivery Sci Technol, 2019, 51:356-363.
[63] Zhang YT, Yu YQ, Yan XX, et al. Different structures of berberine and five other protoberberine alkaloids that affect P-glycoprotein-mediated efflux capacity[J]. Acta Pharmacol Sin, 2019, 40:133-142.
[64] Dewanjee S, Dua TK, Bhattacharjee N, et al. Natural products as alternative choices for P-glycoprotein (P-gp) inhibition[J]. Molecules, 2017, 22:871.
[65] Zhang ZH, Chen Y, Deng J, et al. Solid dispersion of berberine-phospholipid complex/TPGS 1000/SiO2:preparation, characterization and in vivo studies[J]. Int J Pharm, 2014, 465:306-316.
[66] Sun J, Bao H, Peng Y, et al. Improvement of intestinal transport, absorption and anti-diabetic efficacy of berberine by using Gelucire44/14:in vitro, in situ and in vivo studies[J]. Int J Pharm, 2018, 544:46-54.
[67] Shan YQ, Zhu YP, Pang J, et al. Tetrandrine potentiates the hypoglycemic efficacy of berberine by inhibiting P-glycoprotein function[J]. Biol Pharm Bull, 2013, 36:1562-1569.
[68] Narade S, Pore Y. Assessment of permeability berberine chloride across goat intestinal membrane in presence of natural biopotentiator curcumin[J]. Indian Drugs, 2021, 58:23-27.
[69] Elsheikh MA, Elnaggar YSR, Hamdy DA, et al. Novel cremochylomicrons for improved oral bioavailability of the antineoplastic phytomedicine berberine chloride:optimization and pharmacokinetics[J]. Int J Pharm, 2018, 535:316-324.
[70] Xiong W, Sang W, Linghu KG, et al. Dual-functional Brij-S20-modified nanocrystal formulation enhances the intestinal transport and oral bioavailability of berberine[J]. Int J Nanomed, 2018, 13:3781-3793.
[71] Khan I, Joshi G, Nakhate KT, et al. Nano-co-delivery of berberine and anticancer drug using PLGA nanoparticles:exploration of better anticancer activity and in vivo kinetics[J]. Pharm Res, 2019, 36:149-165.
[72] Cheng Z, Chen AF, Wu F, et al. 8,8-Dimethyldihydroberberine with improved bioavailability and oral efficacy on obese and diabetic mouse models[J]. Bioorg Med Chem, 2010, 18:5915-5924.
[73] Chen Z, Ye XL, Yi J, et al. Synthesis of 9-O-glycosyl-berberine derivatives and bioavailability evaluation[J]. Med Chem Res, 2011, 21:1641-1646.
[74] Han LW, Sheng WL, Li XB, et al. Novel carbohydrate modified berberine derivatives:synthesis and in vitro anti-diabetic investigation[J]. MedChemComm, 2019, 10:598-605.
[75] Wang L, Kong H, Jin M, et al. Synthesis of disaccharide modified berberine derivatives and their anti-diabetic investigation in zebrafish using a fluorescence-based technology[J]. Org Biomol Chem, 2020, 18:3563-3574.
[76] Shan YQ, Ren G, Wang YX, et al. Berberine analogue IMB-Y53 improves glucose-lowering efficacy by averting cellular efflux especially P-glycoprotein efflux[J]. Metabolism, 2013, 62:446-456.
[77] Singh N, Sharma B. Toxicological effects of berberine and sanguinarine[J]. Front Mol Biosci, 2018, 5:21.
[78] Mahmoudi M, Rabe SZT, Balali Mood M, et al. Immunotoxicity induced in mice by subacute exposure to berberine[J]. J Immunotoxicol, 2016, 13:255-262.
[79] Rad SZK, Rameshrad M, Hosseinzadeh H. Toxicology effects of Berberis vulgaris (barberry) and its active constituent, berberine:a review[J]. Iran J Basic Med Sci, 2017, 20:516-529.
[80] Cannillo M, Frea S, Fornengo C, et al. Berberine behind the thriller of marked symptomatic bradycardia[J]. World J Cardiol, 2013, 5:261-264.
1.王琰, 蒋建东.肠道菌介导的PK-PD新模式:小檗碱药代动力学引发的思考[J]. 药学学报, 2018,53(5): 659-666
2.胡宇莉, 陈超, 邹宗尧, 李学刚, 叶小利.8-十六烷基小檗碱与小檗碱的大鼠药代动力学和组织分布比较研究[J]. 药学学报, 2014,49(11): 1582-1587
3.杨爽, 王宝莲, 李燕.植物桑的药理研究进展[J]. 药学学报, 2014,49(6): 824-831
4.肖衍宇;宋赟梅;陈志鹏;平其能.水飞蓟宾磷脂复合物的制备与大鼠生物利用度的研究[J]. 药学学报, 2005,40(7): 611-617
5.丁平田;徐晖;郑俊民.微渗析技术在药代动力学和药物代谢研究中的应用[J]. 药学学报, 2002,37(4): 316-320
6.龙超峰;张远;楼雅卿.利福平及异烟肼对家兔体内地西泮药代动力学的影响[J]. 药学学报, 1997,32(7): 481-484
7.王文杰;白金叶;朱秀媛.血浆甘磷酰芥及代谢物的测定方法和大鼠口服药代动力学[J]. 药学学报, 1993,28(10): 738-743
8.曲淑岩;李伟;陈颖莉;孙玉;张艳秋;洪铁.醋柳愈酯的体内代谢及药代动力[J]. 药学学报, 1990,25(9): 664-669
9.曲淑岩;毋英杰;王一华;左玉霞.瑞香素的代谢及药代动力学[J]. 药学学报, 1983,18(7): 496-500