Pharmacologically relevant drug interactions of sulfonylurea antidiabetics with common herbs

Introduction Diabetes mellitus (DM) is a chronic metabolic condition in which hyperglycemia is noted for a longer duration (1). It is a global health burden and the incidence of diabetes among global population is increasing every year. It has been estimated that 171 million of world population were affected by diabetes in the year of 2000 (2), 285 million in 2010 (3), 366 million in 2011 (4), 382 million in 2013 (5), 415 million in 2015 (6) and 451 million in 2017 (7). The prevalence of diabetes around the globe has been projected as 552 million by 2030 (8), 592 million by 2035 (9), 642 million by 2040 (10) and 693 million by 2045 (11). DM is sorted mainly as type 1 DM which is insulindependent (IDDM) and type 2 DM, the non-insulin dependent (NIDDM). DM could be managed by both non-pharmacological and pharmacological therapies. Non-pharmacological management of diabetes includes lifestyle modifications such as dietary interventions, increased physical activity and smoking cessation. (12). Type 1 diabetes is managed pharmacologically by administering insulin injections mainly and the pharmacological management of type 2 diabetes includes the use of antidiabetic medications such as metformin, sulfonylureas, meglitinides (repaglinide and nateglinide), thiazolidinediones (rosiglitazone and pioglitazone), alpha glucosidase inhibitors (acarbose and miglitol), dipeptidyl peptidase 4 (DPP4) inhibitors (sitagliptin, saxagliptin, linagliptin, etc), SGLT2 inhibitors (dapagliflozin, http://www.herbmedpharmacol.com doi: 10.15171/jhp.2018.32


Introduction
Diabetes mellitus (DM) is a chronic metabolic condition in which hyperglycemia is noted for a longer duration (1).It is a global health burden and the incidence of diabetes among global population is increasing every year.It has been estimated that 171 million of world population were affected by diabetes in the year of 2000 (2), 285 million in 2010 (3), 366 million in 2011 (4), 382 million in 2013 (5), 415 million in 2015 (6) and 451 million in 2017 (7).The prevalence of diabetes around the globe has been projected as 552 million by 2030 (8), 592 million by 2035 (9), 642 million by 2040 (10) and 693 million by 2045 (11).DM is sorted mainly as type 1 DM which is insulindependent (IDDM) and type 2 DM, the non-insulin dependent (NIDDM).DM could be managed by both non-pharmacological and pharmacological therapies.Non-pharmacological management of diabetes includes lifestyle modifications such as dietary interventions, increased physical activity and smoking cessation.(12).Type 1 diabetes is managed pharmacologically by administering insulin injections mainly and the pharmacological management of type 2 diabetes includes the use of antidiabetic medications such as metformin, sulfonylureas, meglitinides (repaglinide and nateglinide), thiazolidinediones (rosiglitazone and pioglitazone), alpha glucosidase inhibitors (acarbose and miglitol), dipeptidyl peptidase 4 (DPP4) inhibitors (sitagliptin, saxagliptin, linagliptin, etc), SGLT2 inhibitors (dapagliflozin, canagliflozin, etc.), GLP-1 agonists (exenatide, liraglutide, etc) and amylin analogue (pramlintide) (13).Sulfonylurea antidiabetics reduce the blood sugar levels by inducing the release of insulin from beta cells of pancreas (14).They include first-generation drugs such as Tolbutamide, Chlorpropamide, etc and second-generation drugs like gliclazide, glipizide, glibenclamide, etc (15).Nowadays, the use of complementary and alternative medicine (CAM) is common amongst patients with diabetes and other common chronic problems.It has been estimated that 9.8%-76.0% of general population tend to use CAM, globally (16).The CAM use found high in people such as women, those with literacy, those with employment, those with poor physical health, and those with diabetes or its comorbidities (17).Furthermore, it has been reported that the prevalence of CAM use in patients with diabetes is approximately 48% (18).The most frequently used CAM treatments among patients with diabetes include herbal medicines, nutritional advice, spiritual healing, massage, and meditation (19).Herbal supplement use is getting popular among general population.A study from the United States found that approximately 35% of 26 157 participants used at least one herbal supplement (20).Up to 80% of population in developing countries use traditional herbal medicines as World Health Organization estimated it (21).A study from Saudi Arabia comprising 228 patients with diabetes revealed that 24.6% of participants used herbal supplements (22) and an Iraqi study conducted among 884 diabetic patients found that 17.3% (153 respondents) of them used herbal supplements (23).Drug interaction is defined as the interference of effects of one drug by the co-administered drugs, herbs, alcohol or tobacco smoke (24).The drug interaction leading to undesirable effects such as increased adverse effects or decreased beneficial effects, is termed 'adverse drug interaction' .The patients with diabetes are at heightened risk of adverse drug interactions, as they concomitantly use many medications to manage their comorbidities such as hypertension, dyslipidemia, heart diseases, depression, infections, etc, along with their antidiabetic medications (25).The probability of adverse drug interactions in diabetic patients is particularly high in patients who use sulfonylureas with herbal medicines.The present review is aimed to present the herbal drugs having interacting potentials with sulfonylurea antidiabetics.

Methods
The literature was searched in databases such as PubMed, Google Scholar, Science Direct, Directory of open access journals (DOAJ) and reference lists were searched using the keywords Drug interactions, Sulfonylureas, Pharmacodynamic interactions, Antidiabetic herbs, Pharmacokinetic interactions and CYP2C9.

Results
The herbal supplements taken by diabetic patients may interact with sulfonylureas either pharmacokinetically or pharmacodynamically.Sulfonylurea antidiabetics are metabolised primarily by cytochrome P450 2C9 (CYP2C9) enzyme (26) and by CYP3A4 enzyme to a lesser extent (27).Hence, the herbal drugs capable of modulating CYP enzymes may interact with sulfonylureas, pharmacokinetically (Table 1).As it was stated sulfonylureas are potent antidiabetic drugs and their concomitant use with certain herbs having antidiabetic activity may enhance the risk of hypoglycemia (Table 2).St John's Wort (Hypericum perforatum) St John's Wort is a herbal drug popularly used to treat depression.It can induce many CYP enzymes including CYP3A4 and CYP2C9 (28).The plasma concentrations of gliclazide decreased due to the concomitant use of St John's Wort, which could induce the CYP-mediated metabolism of gliclazide.It is recommended to monitor the signs of reduced hypoglycemic activity of sulfonylureas in patients with diabetes taking the combination of sulfonylureas and St John's Wort (29).

Ginkgo biloba
Ginkgo biloba may be useful to treat some neurological, psychological, and behavioral disorders.The animal (30) and clinical (31) studies have identified that CYP2C9-mediated metabolism of tolbutamide Monitor the signs of reduced hypoglycemic activity of sulfonylureas in patients with diabetes taking the combination of sulfonylureas and St John's Wort (29).

Ginkgo biloba
Ginkgo biloba may decrease the plasma concentrations of sulfonylureas (31).
The hypoglycemic effect of sulfonylureas may be decreased.

Pineapple juice
The pineapple juice may inhibit the CYP2C9-mediated metabolism of sulfonylureas.
The plasma concentrations of sulfonylureas might be elevated by pineapple juice.
Additive reductions in blood glucose may result if sulfonylureas are used in patients consuming bitter melon regularly (43).
Fenugreek use in patients taking sulfonylureas may further decrease the blood glucose levels (53,54).
The dose of sulfonylureas may need to be adjusted if the patient is taking cinnamon concurrently (68).

Concomitant use of sulfonylureas and
Gymnema may result in potentiation of hypoglycemic effects (81, 82).
Ginseng may potentiate the hypoglycemic activity of sulfonylureas (107).
The blood glucose levels should be monitored in patients taking sulfonylureas and ginger together, to avoid the occurrence of hypoglycemia (118).

Garlic (Allium Sativum)
Garlic may decrease the blood glucose levels through direct or indirect stimulation of insulin secretion (123,124), enhanced glucose utilization (125) and slowing down glucose absorption (126).
Caution should be applied in patients taking sulfonylureas and garlic together (127,128).
Aloe vera can potentiate the hypoglycemic effect of sulfonylureas (141).

Sesame oil [Sesamum indicum]
Diabetes patients may prefer sesame oil as it reduces the detrimental effects of diabetes by improving glucose control, blood pressure, lipid levels and cardiac and renal health (149)(150)(151)(152).
Sesame oil may improve hyperglycemia of patients taking sulfonylureas (153).

Andrographis paniculata
Androdrographolide of Andrographis paniculata reduced the plasma glucose in streptozotocin-induced diabetic rats by increasing glucose utilization (154).
Use Andrographis paniculata (Androdrographolide) with caution in patients taking sulfonylureas to avoid the risk of hypoglycemia (155).

Neem (Azadirachta indica)
A. indica found to decrease the blood glucose level by improving carbohydrate metabolism through the stimulation of the β-cells in streptozotocin-induced diabetic mice (157).

Concomitant use of aqueous extract of
A. indica with gliclazide produced good control of blood glucose (158).
is induced significantly by G. biloba extract, resulting in decreased plasma concentrations and reduced hypoglycemic effect of tolbutamide.
Pomegranate (Punica granatum) juice Pomegranate juice may inhibit CYP2C9 activity and increase the plasma concentration of tolbutamide resulting in potentiation of the hypoglycemic effect (32).

Pineapple juice
Pineapple juice contains bromelain as the principal component and it has been shown that CYP2C9 activity is inhibited strongly by Pineapple juice in vitro (33).
The pineapple juice may inhibit the CYP2C9-mediated metabolism of sulfonylureas and elevate their plasma concentrations due to its very strong CYP2C9 inhibitory activity, in vitro.In the following section the possible interaction of sulfonylureas with medicinal plants which have antidiabetic activities are presented.
Additive reductions in blood glucose may result if sulfonylureas are used in patients consuming bitter melon regularly.Potentiation of hypoglycemic activity of glibenclamide was also noted in patients taking bitter melon extract (43).Blood sugar should be monitored and the dosage adjustment of sulfonylureas may be necessary to avoid hypoglycemic complications.
Gymnema (Gymnema sylvestre) Gymnema is a herb found vastly in India and Srilanka.
Active phytoconstituents of Gymnema include triterpene saponins (gymnemic acids and gymnemasaponins, gymnemasides), flavones, anthraquinones, resins, alkaloids, etc (72,73).Gymnemic acids of Gymnema is responsible for the antidiabetic activity.Gymnema may reduce the glucose levels by delaying glucose absorption (74), enhancing insulin secretion (75-77), increasing glucose uptake in the liver, kidney and muscle (78) and inducing repair or regeneration of pancreatic beta cells (79,80).Significant reduction of fasting blood glucose and lipid levels has been noted in patients with type 2 diabetes receiving sulfonylurea treatment along with 400 mg of Gymnema daily for 18 to 20 months (55,79).Concomitant use of sulfonylureas and Gymnema may result in potentiation of hypoglycemic effects (81,82).

Ginger (Zingiber officinale)
Ginger root is used as a cooking spice in foods.

Garlic (Allium sativum)
Garlic is a natural medicinal plant and is used as a flavoring substance in food preparations.Garlic found helpful to lower blood sugar, reduce cholesterol levels, prevent cardiovascular diseases, enhance the immune system and regulate blood pressure.It is effective against bacterial, viral, fungal and parasitic infections (119).The phytochemicals of garlic include sulfur compounds (allicin, alliin and agoene), volatile oils, enzymes (allinase, peroxidase and miracynase), carbohydrates (sucrose and glucose), minerals (selenium), amino acids (cysteine, glutamine, isoleucine and methionine), bioflavonoids (quercetin and cyanidin, allistatin I and allistatin II) and vitamins (C, E, A, niacin, B1 and B2 and betacarotene (120).Sulphur compounds of garlic are linked to the hypoglycemic activity (121,122).Garlic may decrease the blood glucose levels through direct or indirect stimulation of insulin secretion (123,124), enhanced glucose utilization (125) and reduction of glucose absorption (126).
Greater hypoglycemic activity was noted in streptozotocininduced diabetic rats receiving the combination of garlic extract (500 mg/kg) and glibenclamide (0.25 or 0.5 mg/ kg) than either of the drug given alone (127).Caution should be applied in patients taking sulfonylureas and garlic together (127,128).

Andrographis paniculata
Andrographis paniculata is a medicinal plant used traditionally to treat various illnesses like infections, liver problems, diabetes, etc.The principal constituent of A. paniculata is androdrographolide, which has been shown to reduce the plasma glucose in streptozotocin-induced diabetic rats by increasing glucose utilization (154).
The hypoglycemic effect of glyburide enhanced considerably by the coadministration with androdrographolide.The herbal preparations containing A. paniculata (androdrographolide) should be used in patients taking sulfonylureas with special attention to avoid the risk of hypoglycemia (155).

Neem (Azadirachta indica)
Azadirachta indica is a traditionally used medicinal plant, which has anti-inflammatory, immunostimulant and hypoglycemic activities (156).A. indica found to decrease the blood glucose level by improving carbohydrate metabolism through the stimulation of the β-cells in streptozotocin-induced diabetic mice (157).Concomitant use of aqueous extract of A. indica with gliclazide produced good control of blood glucose (158).

Conclusion
Use of herbal medicines to treat diabetes is getting popular around the world.The herbs like St. John's wort and Gingko biloba induce CYP2C9-mediated metabolism of sulfonylureas while the fruit juices like Pomegranate juice and Pineapple juice inhibit their metabolism.In addition, the antidiabetic herbal supplements such as bitter melon, fenugreek, cinnamon, Gymnema, ginseng, ginger, garlic, Aloe vera, sesame, andrographis paniculata and neem potentiate the hypoglycemic activity of sulfonylureas pharmacodynamically.The prescribers and the pharmacists should be aware of the herbs interacting with sulfonylureas to prevent adverse outcomes.

Authors' contributions
NMPM and RB conceived the presented idea.NMPM drafted the manuscript.RB reviewed it.All read and confirmed its publication.

Conflict of interests
None.