Comparative drug-drug interactions of berberine and astragaloside IV in normal and type 2 diabetes mellitus rats based on UPLC-QqQ-MS/MS

Abstract

The UPLC-QqQ-MS/MS method was established, validated, and used for the simultaneous detection of berberine (BBR), astragaloside IV (AST), and the main metabolites to demonstrate the comparative pharmacokinetics of BBR and AST in normal and T2DM rats. BBR and AST had reduced the internal exposure of each other and their main metabolites in normal rats. However, AST had few significant effects on the pharmacokinetic parameters of BBR and the main metabolites in T2DM rats. Similarly, BBR had no significant effect on the pharmacokinetic parameters of AST but significantly increased the exposure to cycloastragenol (CAG) in vivo. Molecular docking of BBR and AST with the P-glycoprotein (P-gp) was performed, which indicated that both BBR and AST are potential substrates for P-gp. The differences in gut microbiota between normal and T2DM rats were compared by 16S rRNA sequencing. Git microbiota that could produce β-glucosidase and β-xylosidase were highly abundant in T2DM rats. The current study indicated that BBR and AST had reduced oral bioavailability. The gut microbiota was enriched in the intestines of T2DM rats and promoted the hydrolysis of AST to produce CAG, while the drug-drug interaction between AST and BBR was blocked.

Keywords

Drug-drug interactions / Berberine / Astragaloside IV / Type 2 diabetes mellitus / UPLC-QqQ-MS/MS

References

[1] Williams R, Karuranga S, Malanda B, Saeedi P, Basit A, Besançon S, et al.: Global and Regional Estimates and Projections of Diabetes-related Health Expenditure: Results from the International Diabetes Federation Diabetes Atlas, 9th Edition. Diabetes Research and Clinical Practice 2020, 162: 108072.

[2] Magliano DJ, Boyko EJ: IDF Diabetes Atlas 10th Edition Scientific Committee, IDF DIABETES ATLAS [Internet], 10th Edition . Brussels: International Diabetes Federation; 2021. Chapter 3, Global Picture.

[3] GBD 2021 Diabetes Collaborators: Global, Regional, and National Burden of Diabetes from 1990 to 2021, with Projections of Prevalence to 2050: A Systematic Analysis for the Global Burden of Disease Study 2021. Lancet 2023, 402: 203-234.

[4] Weng JP, Bi Y: Epidemiological Status of Chronic Diabetic Complications in China. Chinese Medical Journal 2015, 128: 3267-3269.

[5] Riddle MC, Cefalu WT, Evans PH, Gerstein HC, Nauck MA, Oh WK, et al.: Consensus Report: Definition and Interpretation of Remission in Type 2 Diabetes. Diabetes Care 2021, 44: 2438-2444.

[6] Riddle MC, Cefalu WT, Evans PH, Gerstein HC, Nauck MA, Oh WK, et al.: Consensus Report: Definition and Interpretation of Remission in Type 2 Diabetes. Diabetologia 2021, 64: 2359-2366.

[7] Chan SP, Colagiuri S: Systematic Review and Meta-analysis of the Efficacy and Hypoglycemic Safety of Gliclazide Versus Other Insulinotropic Agents. Diabetes Research and Clinical Practice 2015, 110: 75-81.

[8] Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al.: Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. The New England Journal of Medicine 2015, 373: 232-242.

[9] Lalau JD, Kajbaf F, Bennis Y, Hurtel-Lemaire AS, Belpaire F, De Broe ME: Metformin Treatment in Patients With Type 2 Diabetes and Chronic Kidney Disease Stages 3A, 3B, or 4. Diabetes Care 2018, 41: 547-553.

[10] Zaccardi F, Htike ZZ, Webb DR, Khunti K, Davies MJ: Benefits and Harms of Once-Weekly Glucagon-like Peptide-1 Receptor Agonist Treatments: A Systematic Review and Network Meta-analysis. Annals of Internal Medicine 2016, 164: 102-113.

[11] Nauck MA, Wefers J, Meier JJ: Treatment of Type 2 Diabetes: Challenges, Hopes, and Anticipated Successes. The Lancet Diabetes & Endocrinology 2021, 9: 525-544.

[12] Morita Y, Murayama H, Odawara M, Bauer M: Treatment Patterns of Drug-naive Patients with Type 2 Diabetes Mellitus: A Retrospective Cohort Study Using a Japanese Hospital Database. Diabetology & Metabolic Syndrome 2019, 11: 90.

[13] Xu Y, Wang L, He J, Bi Y, Li M, Wang T, et al.: Prevalence and Control of Diabetes in Chinese Adults. JAMA 2013, 310: 948-959.

[14] He H, Deng J, Yang M, An L, Ye X, Li X: Jatrorrhizine from Rhizoma Coptidis Exerts an Anti-obesity Effect in db/db Mice. Journal of Ethnopharmacology 2022, 298: 115529.

[15] Yang Y, Cao S, Xu W, Zang C, Zhang F, Xie Y, et al.: Dual Modulation of Gut Bacteria and Fungi Manifests the Gut-based Anti-hyperlipidemic Effect of Coptidis Rhizoma. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 2022, 153: 113542.

[16] China Pharmacopoeia Committee: Pharmacopoeia of the People’s Republic of China, First Division, 2020 ed. Beijing: China Medical Science and Technology Press; 2020, 1156.

[17] China Pharmacopoeia Committee: Pharmacopoeia of the People’s Republic of China, First Division, 2020 ed. Beijing: China Medical Science and Technology Press; 2020, 1548.

[18] China Pharmacopoeia Committee: Pharmacopoeia of the People’s Republic of China, First Division, 2020 ed . Beijing: China Medical Science and Technology Press; 2020, 1871-1874.

[19] Meng FC, Wu ZF, Yin ZQ, Lin LG, Wang R, Zhang QW: Coptidis Rhizoma and Its Main Bioactive Components: Recent Advances in Chemical Investigation, Quality Evaluation and Pharmacological Activity. Chinese Medicine 2018, 13: 13.

[20] Wang J, Wang L, Lou GH, Zeng HR, Hu J, Huang QW, et al.: Coptidis Rhizoma: a Comprehensive Review of Its Traditional Uses, Botany, Phytochemistry, Pharmacology and Toxicology. Pharmaceutical Biology 2019, 57(1): 193-225.

[21] Fu JY, Zhang Y: Mechanism of Astragali Radix-Coptis Rhizoma Pair in Treating Type 2 Diabetes Mellitus Based on Network Pharmacology. Zhongguo Zhong Yao Za Zhi 2021, 46: 4808-4815.

[22] Ma H, He K, Zhu J, Li X, Ye X: The Anti-hyperglycemia Effects of Rhizoma Coptidis Alkaloids: A Systematic Review of Modern Pharmacological Studies of the Traditional Herbal Medicine. Fitoterapia 2019, 134: 210-220.

[23] Kong WJ, Vernieri C, Foiani M, Jiang JD: Berberine in the Treatment of Metabolism-related Chronic Diseases: A Drug Cloud (dCloud) Effect to Target Multifactorial Disorders. Pharmacology & Therapeutics 2020, 209: 107496.

[24] Wang Y, Shou JW, Li XY, Zhao ZX, Fu J, He CY, et al.: Berberine-induced Bioactive Metabolites of the Gut Microbiota Improve Energy Metabolism. Metabolism 2017, 70: 72-84.

[25] Zhang H, Wei J, Xue R, Wu JD, Zhao W, Wang ZZ, et al.: Berberine Lowers Blood Glucose in Type 2 Diabetes Mellitus Patients through Increasing Insulin Receptor Expression. Metabolism 2010, 59: 285-292.

[26] Wang C, Yuan Z, Xie J, Lei Y, Li Y, Huang J, et al.: Integrated Metabolomics and Molecular Docking Reveal Berberrubine Inhibits Thrombosis by Regulating the Vitamin K Catalytic Cycle in Mice. European Journal of Pharmacology 2023, 938: 175436.

[27] Bolyen E, Rideout JR, Dillon MR, Bokulich NA, Abnet CC, Al-Ghalith GA, et al.: Reproducible, Interactive, Scalable and Extensible Microbiome Data Science Using QIIME 2. Nature Biotechnology 2019, 37: 852-857.

[28] Nossa CW, Oberdorf WE, Yang L, Aas JA, Paster BJ, Desantis TZ, et al.: Design of 16S rRNA Gene Primers for 454 Pyrosequencing of the Human Foregut Microbiome. World Journal of Gastroenterology 2010, 16: 4135-4144.

[29] Mora Lagares L, Minovski N, Caballero Alfonso AY, Benfenati E, Wellens S, Culot M, et al.: Homology Modeling of the Human P-glycoprotein (ABCB1) and Insights into Ligand Binding through Molecular Docking Studies. International Journal of Molecular Sciences 2020, 21: 4058.

[30] Rosano C, Viale M, Cosimelli B, Severi E, Gangemi R, Ciogli A, et al.: ABCB1 Structural Models, Molecular Docking, and Synthesis of New Oxadiazolothiazin-3-one Inhibitors. ACS Medicinal Chemistry Letters 2013, 4: 694-698.

[31] Tao JH, Wang DG, Yang C, Huang JH, Qiu WQ, Zhao X: Biotransformation of Luteoloside by a Newly Isolated Human Intestinal Bacterium Using UHPLC-Q-TOF/MS. Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences 2015, 991: 1-8.

[32] Tao JH, Duan JA, Jiang S, Qian YY, Qian DW: Biotransformation and Metabolic Profile of Buddleoside with Human Intestinal Microflora by Ultrahigh-performance Liquid Chromatography Coupled to Hybrid Linear Ion Trap/Orbitrap Mass Spectrometer. Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences 2016, 1025: 7-15.

[33] Yang J, Qian D, Jiang S, Shang EX, Guo J, Duan JA: Identification of Rutin Deglycosylated Metabolites Produced by Human Intestinal Bacteria Using UPLC-Q-TOF/MS. Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences 2012, 898: 95-100.

[34] Campos E, Negro Alvarez MJ, Sabarís di Lorenzo G, Gonzalez S, Rorig M, Talia P, et al.: Purification and Characterization of a GH43 β-xylosidase from Enterobacter sp. Identified and Cloned from Forest Soil Bacteria. Microbiological Research 2014, 169: 213-220.

[35] Watanabe A, Hiraga K, Suda M, Yukawa H, Inui M: Functional Characterization of Corynebacterium Alkanolyticum β-Xylosidase and Xyloside ABC Transporter in Corynebacterium Glutamicum. Applied and Environmental Microbiology 2015, 81: 4173-4183.

[36] Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, et al.: Berberine is a Novel Cholesterol-lowering Drug Working through a Unique Mechanism Distinct from Statins. Nature Medicine 2004, 10: 1344-1351.

[37] Kong WJ, Wei J, Zuo ZY, Wang YM, Song DQ, You XF, et al.: Combination of Simvastatin with Berberine Improves the Lipid-lowering Efficacy. Metabolism, 2008, 57: 1029-1037.

[38] Ren G, Guo JH, Qian YZ, Kong WJ, Jiang JD: Berberine Improves Glucose and Lipid Metabolism in HepG2 Cells Through AMPKα1 Activation. Frontiers in Pharmacology 2020, 11: 647.

[39] Wang C, Wang Y, Ma SR, Zuo ZY, Wu YB, Kong WJ, et al.: Berberine Inhibits Adipocyte Differentiation, Proliferation and Adiposity through Down-regulating Galectin-3. Scientific Reports 2019, 9: 13415.

[40] Ma SR, Tong Q, Lin Y, Pan LB, Fu J, Peng R, et al.: Berberine Treats Atherosclerosis via a Vitamine-like Effect Down-regulating Choline-TMA-TMAO Production Pathway in Gut Microbiota. Signal Transduction and Targeted Therapy 2022, 7: 207.

[41] Wang Y, Tong Q, Shou JW, Zhao ZX, Li XY, Zhang XF, et al.: Gut Microbiota-Mediated Personalized Treatment of Hyperlipidemia Using Berberine. Theranostics 2017, 7: 2443-2451.