Synergistic Behavior of Phytophenolics with Antidiabetic Drugs

  • Muddasarul Hoda
  • Shanmugam Hemaiswarya
  • Mukesh Doble


Diabetes is a highly complex disease with multiple metabolic changes. So a single disease management strategy is ineffective in controlling it and its related risk factors. Common conventional hypoglycemic drugs cause side effects and toxicities. Combination therapy is the best strategy to address multitargeting of the complex metabolic disease and to reduce the dose of the drug and hence the related toxicity/side effect. With the growth of herbal market, there are several reports on herb and drug interactions through pharmacokinetic and pharmacodynamic modes which can be either synergistic or antagonistic in nature. This chapter elaborates on the interaction of herb or a phytochemical with the oral diabetic drugs where the combination differs pharmacokinetically or pharmacodynamically than that of the individual compounds. There is an urgent need in the clinical studies and management of herb and drug combinations to understand both the beneficial and harmful interactions.


Combination therapy Herb–drug interactions Pharmacodynamics Synergy Antagonism Additive 


  1. Abdi H, Azizi F, Amouzegar A (2018) Insulin monotherapy versus insulin combined with other glucose-lowering agents in type 2 diabetes: a narrative review. Int J Endocrinol Metab 16:e65600. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Adisakwattana S, Lerdsuwankij O, Poputtachai U et al (2011) Inhibitory activity of cinnamon bark species and their combination effect with Acarbose against intestinal $α$-glucosidase and pancreatic $α$-amylase. Plant Foods Hum Nutr 66:143–148. CrossRefPubMedGoogle Scholar
  3. Akkarachiyasit S, Charoenlertkul P, Yibchok-anun S, Adisakwattana S (2010) Inhibitory activities of Cyanidin and its glycosides and synergistic effect with Acarbose against intestinal α-glucosidase and pancreatic α-amylase. Int J Mol Sci 11:3387–3396. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Akkarachiyasit S, Yibchok-Anun S, Wacharasindhu S, Adisakwattana S (2011) In vitro inhibitory effects of cyandin-3-rutinoside on pancreatic α-amylase and its combined effect with acarbose. Molecules 16:2075–2083. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Ao Y, Chen J, Yue J, Peng R-X (2008) Effects of 18α-glycyrrhizin on the pharmacodynamics and pharmacokinetics of glibenclamide in alloxan-induced diabetic rats. Eur J Pharmacol 587:330–335. CrossRefPubMedGoogle Scholar
  6. Baradaran A, Rafieian-Kopaei M (2013) Histopathological study of the combination of metformin and garlic juice for the attenuation of gentamicin renal toxicity in rats. J Ren Inj Prev 2:15–21. CrossRefPubMedGoogle Scholar
  7. Boath AS, Stewart D, McDougall GJ (2012) Berry components inhibit α-glucosidase in vitro: synergies between acarbose and polyphenols from black currant and rowanberry. Food Chem 135:929–936. CrossRefPubMedGoogle Scholar
  8. Bunyapraphatsara N, Yongchaiyudha S, Rungpitarangsi V, Chokechaijaroenporn O (1996) Antidiabetic activity of Aloe vera L. juice II. Clinical trial in diabetes mellitus patients in combination with glibenclamide. Phytomedicine 3:245–248. CrossRefPubMedGoogle Scholar
  9. Cekic V, Vasovic V, Jakovljevic V et al (2011) Effect of chromium enriched fermentation product of barley and brewer’s yeast and its combination with rosiglitazone on experimentally induced hyperglycaemia in mice. Srp Arh Celok Lek 139:610–618CrossRefGoogle Scholar
  10. Chang H, Wallis M, Tiralongo E (2007) Use of complementary and alternative medicine among people living with diabetes: literature review. J Adv Nurs 58:307–319. CrossRefPubMedGoogle Scholar
  11. Chávez-Silva F, Cerón-Romero L, Arias-Durán L et al (2018) Antidiabetic effect of Achillea millefollium through multitarget interactions: α-glucosidases inhibition, insulin sensitization and insulin secretagogue activities. J Ethnopharmacol 212:1–7. CrossRefPubMedGoogle Scholar
  12. Chen H-Y, Ye X-L, Cui X-L et al (2012) Cytotoxicity and antihyperglycemic effect of minor constituents from Rhizoma Coptis in HepG2 cells. Fitoterapia 83:67–73. CrossRefPubMedGoogle Scholar
  13. Chen Y, Zhang Y, Dai Y, Tang Z (2018) Systems pharmacology approach reveals the antiinflammatory effects of Ampelopsis grossedentata on dextran sodium sulfate-induced colitis. World J Gastroenterol 24:1398–1409. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Chou T (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58:621–681. CrossRefPubMedGoogle Scholar
  15. Chou T-C, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul 22:27–55. CrossRefGoogle Scholar
  16. Choudhari VP, Gore KP, Pawar AT (2017) Antidiabetic, antihyperlipidemic activities and herb–drug interaction of a polyherbal formulation in streptozotocin induced diabetic rats. J Ayurveda Integr Med 8:218–225. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Elango H, Ponnusankar S, Sundaram S (2015) Assessment of Pharmacodynamic and pharmacokinetic interaction of aqueous extract of Cassia auriculata L. and metformin in rats. Pharmacogn Mag 11:S423–S426. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Erejuwa OO, Sulaiman SA, Wahab MSA et al (2011) Glibenclamide or metformin combined with honey improves glycemic control in streptozotocin-induced diabetic rats. Int J Biol Sci 7:244–252CrossRefGoogle Scholar
  19. Ezuruike U, Prieto JM (2016) Assessment of potential herb-drug interactions among Nigerian adults with Type-2 diabetes. Front Pharmacol 7:248. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Feng L, Luo H, Xu Z et al (2016) Bavachinin, as a novel natural pan-PPAR agonist, exhibits unique synergistic effects with synthetic PPAR-gamma and PPAR-alpha agonists on carbohydrate and lipid metabolism in db/db and diet-induced obese mice. Diabetologia 59:1276–1286. CrossRefPubMedGoogle Scholar
  21. Festa A, Hanley AJ, Tracy RP et al (2003) Inflammation in the Prediabetic state is related to increased insulin resistance rather than decreased insulin secretion. Circulation 108:1822CrossRefGoogle Scholar
  22. Gao J, Xu P, Wang Y et al (2013) Combined effects of green tea extracts, green tea polyphenols or epigallocatechin Gallate with Acarbose on inhibition against α-amylase and α-glucosidase in vitro. Mol 18:11614CrossRefGoogle Scholar
  23. Han C, Liu T (2009) A comparison of hypoglycemic activity of three species of Basidiomycetes rich in vanadium. Biol Trace Elem Res 127:177–182. CrossRefPubMedGoogle Scholar
  24. Hassanzadeh-Taheri M, Hassanpour-Fard M, Doostabadi M et al (2018) Co-administration effects of aqueous extract of turnip leaf and metformin in diabetic rats. J Tradit Complement Med 8:178–183. CrossRefPubMedGoogle Scholar
  25. He Y-L, Ito H, Yamaguchi M et al (2012) Effects of meal timing relative to dosing on the pharmacokinetics and pharmacodynamics of vildagliptin in Japanese patients with type 2 diabetes. Int J Clin Pharmacol Ther 50:237–247CrossRefGoogle Scholar
  26. Hermann R, von Richter O (2012) Clinical evidence of herbal drugs as perpetrators of pharmacokinetic drug interactions. Planta Med 78:1458–1477. CrossRefPubMedGoogle Scholar
  27. Itagaki S, Kobayashi Y, Otsuka Y et al (2005) Food-drug interaction between ferulic acid and nateglinide involving the fluorescein/H+ cotransport system. J Agric Food Chem 53:2499–2502. CrossRefPubMedGoogle Scholar
  28. Kamble B, Gupta A, Moothedath I et al (2016) Effects of Gymnema sylvestre extract on the pharmacokinetics and pharmacodynamics of glimepiride in streptozotocin induced diabetic rats. Chem Biol Interact 245:30–38. CrossRefPubMedGoogle Scholar
  29. Kammalla AK, Ramasamy MK, Chintala J et al (2015a) Comparative pharmacokinetic interactions of quercetin and Rutin in rats after oral administration of European patented formulation containing Hipphophae rhamnoides and co-administration of quercetin and Rutin. Eur J Drug Metab Pharmacokinet 40:277–284. CrossRefPubMedGoogle Scholar
  30. Kammalla AK, Ramasamy MK, Inampudi J et al (2015b) Comparative pharmacokinetic study of Mangiferin after Oral Administration of Pure Mangiferin and US patented Polyherbal formulation to rats. AAPS PharmSciTech 16:250–258. CrossRefPubMedGoogle Scholar
  31. Karara AH, Dunning BE, McLeod JF (1999) The effect of food on the oral bioavailability and the pharmacodynamic actions of the insulinotropic agent nateglinide in healthy subjects. J Clin Pharmacol 39:172–179CrossRefGoogle Scholar
  32. Kasichayanula S, Liu X, Zhang W et al (2011) Effect of a high-fat meal on the pharmacokinetics of dapagliflozin, a selective SGLT2 inhibitor, in healthy subjects. Diabetes Obes Metab 13:770–773. CrossRefPubMedGoogle Scholar
  33. Kunasegaran T, DD M, Achike F, Mustafa M (2014) Effects of quercetin and metformin combination on the reactivity of aortic tTissues from rats with Type-2 diabetesGoogle Scholar
  34. Kunasegaran T, Mustafa MR, Achike FI, Murugan DD (2017) Quercetin and pioglitazone synergistically reverse endothelial dysfunction in isolated aorta from fructose-streptozotocin (F-STZ)-induced diabetic rats. Eur J Pharmacol 799:160–170. CrossRefPubMedGoogle Scholar
  35. Lau K-M, Lai K-K, Liu C-L et al (2012) Synergistic interaction between Astragali Radix and Rehmanniae Radix in a Chinese herbal formula to promote diabetic wound healing. J Ethnopharmacol 141:250–256. CrossRefPubMedGoogle Scholar
  36. Lee Y-C, Chang C-H, Dong Y-H et al (2017) Comparing the risks of hospitalized heart failure associated with glinide, sulfonylurea, and acarbose use in type 2 diabetes: a nationwide study. Int J Cardiol 228:1007–1014. CrossRefPubMedGoogle Scholar
  37. Liu X-H, Li X-M, Han C-C et al (2015) Effects of combined therapy with glipizide and Aralia root bark extract on glycemic control and lipid profiles in patients with type 2 diabetes mellitus. J Sci Food Agric 95:739–744. CrossRefPubMedGoogle Scholar
  38. Mamindla S, Koganti VSRGP, Ravouru N, Koganti B (2017) Effect of Cinnamomum cassia on the pharmacokinetics and pharmacodynamics of pioglitazone. Curr Clin Pharmacol 12:41–49. CrossRefPubMedGoogle Scholar
  39. Meng Q, Liu K (2014) Pharmacokinetic interactions between herbal medicines and prescribed drugs: focus on drug metabolic enzymes and transporters. Curr Drug Metab 15:791–807CrossRefGoogle Scholar
  40. Miyazaki Y, Matsuda M, DeFronzo RA (2002) Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes Care 25:517 LP–517523. CrossRefGoogle Scholar
  41. Nankar R, Doble M (2015) Ellagic acid potentiates insulin sensitising activity of pioglitazone in L6 myotubes, 15, 1Google Scholar
  42. Nankar R, Doble M (2017) Hybrid drug combination: anti-diabetic treatment of type 2 diabetic Wistar rats with combination of ellagic acid and pioglitazoneGoogle Scholar
  43. Nasrolahi O, Heidari R, Rahmani F, Farokhi F (2012) Effect of natural honey from Ilam and metformin for improving glycemic control in streptozotocin-induced diabetic rats. Avicenna J Phytomedicine 2:212–221Google Scholar
  44. Nivitabishekam SN, Asad M, Prasad VS (2009) Pharmacodynamic interaction of Momordica charantia with rosiglitazone in rats. Chem Biol Interact 177:247–253. CrossRefPubMedGoogle Scholar
  45. Olurishe C, Kwanashie H, Zezi A et al (2016) Chronic administration of ethanol leaf extract of Moringa oleifera lam. (Moringaceae) may compromise glycaemic efficacy of Sitagliptin with no significant effect in retinopathy in a diabetic rat model. J Ethnopharmacol 194:895–903. CrossRefPubMedGoogle Scholar
  46. Poonam T, Prem Prakash G, Vijay Kumar L (2013) Interaction of Momordica Charantia with metformin in diabetic ratsGoogle Scholar
  47. Prabhakar PK, Doble M (2009a) Synergistic effect of phytochemicals in combination with hypoglycemic drugs on glucose uptake in myotubes. Phytomedicine 16:1119–1126. CrossRefPubMedGoogle Scholar
  48. Prabhakar PK, Doble M (2009b) Synergistic effect of phytochemicals in combination with hypoglycemic drugs on glucose uptake in myotubes. Phytomedicine 16:1119–1126. CrossRefPubMedGoogle Scholar
  49. Prabhakar PK, Doble M (2011a) Interaction of phytochemicals with hypoglycemic drugs on glucose uptake in L6 myotubes. Phytomedicine 18:285–291. CrossRefPubMedGoogle Scholar
  50. Prabhakar PK, Doble M (2011b) Effect of natural products on commercial Oral antidiabetic drugs in enhancing 2-Deoxyglucose uptake by 3T3-L1 adipocytes. Ther Adv Endocrinol Metab 2:103–114. CrossRefPubMedPubMedCentralGoogle Scholar
  51. Prabhakar PK, Prasad R, Ali S, Doble M (2013) Synergistic interaction of ferulic acid with commercial hypoglycemic drugs in streptozotocin induced diabetic rats. Phytomedicine 20:488–494. CrossRefPubMedGoogle Scholar
  52. Prescrire International (2014) Type 2 diabetes and metformin. First choice for monotherapy: weak evidence of efficacy but well-known and acceptable adverse effects. Prescrire Int 23:269–272Google Scholar
  53. Rafieian-Kopaei M, Baradaran A (2013) Combination of metformin with other antioxidants may increase its renoprotective efficacy. J Ren Inj Prev 2:35–36. CrossRefPubMedGoogle Scholar
  54. Ríos JL, Francini F, Schinella GR (2015) Natural products for the treatment of type 2 diabetes mellitus. Planta Med 81:975–994. CrossRefPubMedGoogle Scholar
  55. Rutter MK, Meigs JB, Sullivan LM et al (2005) Insulin resistance, the metabolic syndrome, and incident cardiovascular events in the Framingham offspring study. Diabetes 54:3252 LP–3253257CrossRefGoogle Scholar
  56. Sahu R, Ahmed T, Sangana R et al (2018) Effect of Tinospora cordifolia aqua-alcoholic extract on pharmacokinetic of Glibenclamide in rat: an herb-drug interaction study. J Pharm Biomed Anal 151:310–316. CrossRefPubMedGoogle Scholar
  57. Saito Y, Itagaki S, Otsuka Y et al (2005) Substrate specificity of the nateglinide/H(+) cotransport system for phenolic acids. J Agric Food Chem 53:6100–6104. CrossRefPubMedGoogle Scholar
  58. Samala S, Veeresham C (2016) Pharmacokinetic and Pharmacodynamic interaction of Boswellic acids and Andrographolide with glyburide in diabetic rats: including its PK/PD modeling. Phytother Res 30:496–502. CrossRefPubMedGoogle Scholar
  59. Sankar D, Ali A, Sambandam G, Rao R (2011) Sesame oil exhibits synergistic effect with anti-diabetic medication in patients with type 2 diabetes mellitus. Clin Nutr 30:351–358. CrossRefPubMedGoogle Scholar
  60. Satoh T, Igarashi M, Yamada S et al (2015) Inhibitory effect of black tea and its combination with acarbose on small intestinal α-glucosidase activity. J Ethnopharmacol 161:147–155. CrossRefPubMedGoogle Scholar
  61. Scheen AJ (2007) Drug-drug and food-drug pharmacokinetic interactions with new insulinotropic agents repaglinide and nateglinide. Clin Pharmacokinet 46:93–108. CrossRefPubMedGoogle Scholar
  62. Shengule S, Kumbhare K, Patil D et al (2018) Herb-drug interaction of Nisha Amalaki and Curcuminoids with metformin in normal and diabetic condition: a disease system approach. Biomed Pharmacother 101:591–598. CrossRefPubMedGoogle Scholar
  63. Shi Z, Gao J, Yuan Y et al (2014) Effect of raw Radix Rehmanniae on the pharmacokinetics of pioglitazone in rats. Pak J Pharm Sci 27:537–539PubMedGoogle Scholar
  64. Srujan K, Ramakrishna R, Jumar DS (2014) Effect of Gymnema sylvestre extract on the pharmacokinetics and pharmacodynamics of oral hypoglycemic drug—metformin in hyperglycemic rats. J Pharm Res 8:614–620Google Scholar
  65. Stage TB, Pedersen RS, Damkier P et al (2015) Intake of St John’s wort improves the glucose tolerance in healthy subjects who ingest metformin compared with metformin alone. Br J Clin Pharmacol 79:298–306. CrossRefPubMedPubMedCentralGoogle Scholar
  66. Tongia A, Tongia SK, Dave M (2004) Phytochemical determination and extraction of Momordica charantia fruit and its hypoglycemic potentiation of oral hypoglycemic drugs in diabetes mellitus (NIDDM). Indian J Physiol Pharmacol 48:241–244PubMedGoogle Scholar
  67. Triplitt C (2006) Drug interactions of medications commonly used in diabetes. Diabetes Spectr 19:202 LP–202211CrossRefGoogle Scholar
  68. Van de Laar FA, Lucassen PL, Akkermans RP et al (2005) Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev.
  69. Vatsavai LK, Kilari EK (2016) Influence of curcumin on the pharmacodynamics and pharmacokinetics of gliclazide in animal models. J Exp Pharmacol 8:69–76. CrossRefPubMedPubMedCentralGoogle Scholar
  70. Veeresham C, Sujatha S, Rani TS (2012) Effect of piperine on the pharmacokinetics and pharmacodynamics of glimepiride in normal and streptozotocin-induced diabetic rats. Nat Prod Commun 7:1283–1286PubMedGoogle Scholar
  71. Vigneri P, Frasca F, Sciacca L et al (2009) Diabetes and cancer. Endocr Relat Cancer 16:1103–1123. CrossRefPubMedGoogle Scholar
  72. Waisundara VY, Hsu A, Huang D, Tan BK-H (2008) Scutellaria baicalensis enhances the anti-diabetic activity of metformin in streptozotocin-induced diabetic Wistar rats. Am J Chin Med 36:517–540. CrossRefPubMedGoogle Scholar
  73. Wallace AW, Amsden GW (2002) Is it really OK to take this with food? Old interactions with a new twist. J Clin Pharmacol 42:437–443. CrossRefPubMedGoogle Scholar
  74. Wang X, Chen Y, Abdelkader D, Hassan W, Sun H, Jun L (2015) Combination therapy with Oleanolic acid and metformin as a synergistic treatment for diabetes. J Diabetes Res 2015:12. CrossRefGoogle Scholar
  75. Xiao B-X, Wang Q, Fan L-Q et al (2014) Pharmacokinetic mechanism of enhancement by Radix Pueraria flavonoids on the hyperglycemic effects of cortex Mori extract in rats. J Ethnopharmacol 151:846–851. CrossRefPubMedGoogle Scholar
  76. Yim S, You BH, Chae H-S et al (2017) Multidrug and toxin extrusion protein 1-mediated interaction of metformin and Scutellariae radix in rats. Xenobiotica 47:998–1007. CrossRefPubMedGoogle Scholar
  77. Yoon SH, Han EJ, Sung JH, Chung SH (2007) Anti-diabetic effects of compound K versus metformin versus compound K-metformin combination therapy in diabetic db/db mice. Biol Pharm Bull 30:2196–2200CrossRefGoogle Scholar
  78. Yoshida H, Tsuhako R, Atsumi T et al (2017) Naringenin interferes with the anti-diabetic actions of pioglitazone via pharmacodynamic interactions. J Nat Med 71:442–448. CrossRefPubMedGoogle Scholar
  79. You BH, Chin Y-W, Kim H et al (2018) Houttuynia cordata extract increased systemic exposure and liver concentrations of metformin through OCTs and MATEs in rats. Phyther Res 32:1004–1013. CrossRefGoogle Scholar
  80. Yuan Y, Gao J, Shi Z et al (2012) Herb-drug pharmacokinetic interaction between radix astragali and pioglitazone in rats. J Ethnopharmacol 144:300–304. CrossRefPubMedGoogle Scholar
  81. Zeng L, Zhang G, Lin S, Gong D (2016) Inhibitory mechanism of Apigenin on α-glucosidase and synergy analysis of flavonoids. J Agric Food Chem 64:6939–6949. CrossRefPubMedGoogle Scholar
  82. Zhang B, Li X, Sun W et al (2017a) Dietary flavonoids and Acarbose synergistically inhibit α-glucosidase and lower postprandial blood glucose. J Agric Food Chem 65:8319–8330. CrossRefPubMedGoogle Scholar
  83. Zhang B, Sang Y, Sun W et al (2017b) Combination of flavonoids from Oroxylum indicum seed extracts and acarbose improves the inhibition of postprandial blood glucose: in vivo and in vitro study. Biomed Pharmacother 91:890–898. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Muddasarul Hoda
    • 1
    • 2
  • Shanmugam Hemaiswarya
    • 1
  • Mukesh Doble
    • 1
  1. 1.Department of BiotechnologyIndian Institute of Technology MadrasChennaiIndia
  2. 2.Department of Biological SciencesAliah UniversityKolkataIndia

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