Hesperidin
Hesperidin/Drug Interactions:
AnalgesicsAnalgesics: In animal study, the sedative action of hesperidin appeared to be mediated, in part, by an opioid mechanism which makes combined use beneficial for not only sedation but also pain management (26). Hesperidin produced an analgesic effect in mice (26). AntibioticsAntibiotics: In vitro, hesperidin was found to have antibacterial activity against methicillin-sensitive and methicillin-resistant Staphylococcus aureus isolates; however, this effect was reversed by beta-lactam antibiotics methicillin, penicillin, and oxacillin but not cefoxitin (48). Anticoagulants and antiplateletsAnticoagulants and antiplatelets: In vitro, hesperidin has been found to inhibit platelet aggregation by inhibiting PLC-gamma2 phosphorylation and cyclooxygenase-1 activity (16). Anticonvulsant agentsAnticonvulsant agents: In vitro, hesperidin antagonized the effects of 4-aminopyridine (4-AP) and bicuculline (22). Antidiabetic agentsAntidiabetic agents: In human study, Daflon? (a hesperidin-containing product) has been found to lower blood glucose (18). In animal study, hesperidin prevented hyperglycemia and reduced blood glucose, in part, by increasing hepatic glycolysis and glycogen concentration or by lowering hepatic gluconeogenesis (21; 27). It was also found to increase hepatic glucokinase activity, reduce hepatic glucose transporter 2 protein expression, and elevate the expression of adipocyte glucose transporter 4 and hepatic and adipocyte peroxisome proliferator-activated receptor gamma in animal study,(19; 27; 21). AntihistaminesAntihistamines: In vitro study, 50% methanol extract of Citrus unshiu exerted inhibitory activity against histamine release from basophils of human subjects (49). AntihypertensivesAntihypertensives: In animal study, glucosyl hesperidin enhanced endothelium-dependent vasodilation in response to acetylcholine and reduced oxidative stress (17). Antilipemic agentsAntilipemic agents: In human study, Daflon? (a hesperidin-containing product) has been found to lower total cholesterol, LDL-cholesterol, and triglycerides (18). In animal study, hesperidin has been found to lower plasma and hepatic triglyceride and cholesterol levels (19; 20; 21). Anti inflammatory agentsAnti inflammatory agents: In animal study, hesperidin produced limited anti-inflammatory effects in rats with experimental arthritis (50). It has been speculated that hesperidin may inhibit cyclooxygenase (COX) 2 based on in vitro studies (51). In animal study, synergistic effects were noted with the combined use of neohesperidin or hesperidin and prednisolone (52; 53). Antineoplastic agentsAntineoplastic agents: In vitro, hesperidin has demonstrated anticarcinogenic effects (51; 54; 55; 56; 57; 58; 59; 60; 61; 62). In mouse bone marrow cells, hesperidin protected against cyclophosphamide-induced genotoxicity through antioxidant mechanisms (63). Hesperidin is an active ingredient in the Japanese herbal combination product, rikkunshito. Rikkunshito also consists of eight herbs. Coadministration of rikkunshito and a 5-HT2C receptor antagonist (SB242084HCl) resulted in suppressed cisplatin-induced anorexia by inhibiting growth hormone secretagogue receptor 1a (GHS-R1a) mRNA signal transduction in the hypothalamus (64); the effects of hesperidin alone, however, are unclear using this combination Antiviral agentsAntiviral agents: In vitro, hesperidin protected against the action of influenza virus in HeLa cells (65). Cardiovascular agentsCardiovascular agents: Hesperidin exerted antiatherogenic effects in vitro (23). In human umbilical vein endothelial cells, hesperidin inhibited strain-induced endothelin-1 secretion, increased the formation of reactive oxygen species, and extracellular signal-regulated kinase (ERK) phosphorylation (24). In human study, Cirkan, a venotonic drug containing Ruscus aculeatus (plant extract), hesperidine methylchalcone (flavonoid) and vitamin C, was found to decrease capillary limb diameter and improve capillary morphology (66). CeliprololCeliprolol: In animal study, concomitant administration of hesperidin with celiprolol injection reduced the absorption of celiprolol; area-under-the-curve (AUC) decreased by 75% (28). CyclophosphamideCyclophosphamide: In mouse bone marrow cells, hesperidin was found to reduce oxidative stress and genotoxicity induced by cyclophosphamide (63). Calcium channel blockersCalcium channel blockers: In animal study, hesperidin has been found to enhance the bioavailability of non-dihydropyridine calcium channel blockers including verapamil and diltiazem (29; 30). In animal study, hesperidin enhanced the bioavailability of diltiazem likely due to increased intestinal absorption and reduced the first-pass metabolism of diltiazem in the intestine and in the liver via an inhibition of cytochrome P450 3A or P-glycoprotein (29). Hesperidin enhanced the bioavailability of verapamil after oral administration of Hesperidin in animal study likely due to decreased efflux and metabolism of verapamil in the intestine (30). CNS depressantsCNS depressants: In animal study, sedative action, sleep, and antinociceptive action increased with hesperidin and a benzodiazepine (26). Synergy was shown for hesperidin and diazepam (in fixed ratios of 13:1 and 4:1, as doses that produced 50% effect) for the three sedative effects in the hole board test (25). Time increased for sleep following sodium thiopental, in less of a dose than that for hypnotic effect, and prior injection of hesperidin with diazepam in respective doses that individually were without such enhancement of sleep. Hesperidin's antinociceptive effect increased with injection of hesperidin and an ineffective dose of alprazolam before nociceptive induction; the concurrent doses potentiated hesperidin's effect of reduction in the number of times mice writhed (26). In animal study, the sedative action of hesperidin appeared to be mediated, in part, by an opioid mechanism which makes combined use beneficial for not only sedation but also pain management (26). Cytochrome P450 metabolized agentsCytochrome P450 metabolized agents: Hesperidin, which has a lower level of furanocoumarins compared to other flavonoids, displayed weak inhibitory effects against cytochrome P450 2C9, 2D6, and 3A4 in vitro (31). In animal study, hesperidin was found to enhance the bioavailability of diltiazem likely due to increased intestinal absorption and reduced the first-pass metabolism of diltiazem in the intestine and in the liver via an inhibition of cytochrome P450 3A or P-glycoprotein (29). Dental and periodontal agentsDental and periodontal agents: A hesperidin-loaded microemulsion enhanced permeation compared to the aqueous and isopropyl myristate suspension in vitro; in vivo, the hesperidin-loaded microemulsion displayed topical whitening effects and diminished skin irritation compared to the non-treatment group (67). Drugs used for osteoporosisDrugs used for osteoporosis: In animal study, hesperidin demonstrated beneficial effects on bone (68; 69; 20). Gastrointestinal agentsGastrointestinal agents: The combination of Fructus aurantii Immaturus and Radix Paeoniae alba has been used for gastrointestinal disorders and has displayed bilateral effects. Hesperidin and synephrine are constituents found in this combination. Hesperidin has been found to stimulate gastrointestinal movement via histamine (H1) receptor while synephrine has been found to inhibit through the alpha-adrenergic receptor. In animal study, the bilateral effect of this combination was found to occur through regulation on NF-kappa B p65 translocation and NO production through alpha-adrenergic receptor and H1 receptor (70). Hepatotoxic agentsHepatotoxic agents: In animal study, hesperidin has shown the following effects in the liver: may decrease apoptotic cells, decrease in the precipitation of fibrin in blood vessels, prevention of hepatocyte death related to thrombosis in the liver (71), protective effects against sodium arsenite's acute toxicity (72), and attenuation of hepatotoxicity of lipopolysaccharide (LPS) (73). MethotrexateMethotrexate: In animal study, purified micronized flavonoid fraction (Detralex) was found to increase the efficacy of methotrexate basal treatment due, in part, to the beneficial effects that Detralex? has on microcirculation in the venules and lymphatic vessels (74). Nephrotoxic agentsNephrotoxic agents: In animal study, hesperidin produced protective effects in the kidney against sodium arsenite toxicity (decreases in vacuolation of tubular epithelium, interstitial blood) (72), and carbon tetrachloride's effects (75). Neurologic agentsNeurologic agents: In laboratory study, hesperidin and neohesperidin protected against H2O2-induced cytotoxicity in PC12 cells (76). Opiate antagonistsOpiate antagonists: In mice, the opioid antagonist, naltrexone, blocked the effects of hesperidin on locomotion and partially antagonized hesperidin-induced effects on locomotor activity (26). P-glycoprotein-regulated drugsP-glycoprotein-regulated drugs: In human colon and leukemia cell lines, hesperidin and neohesperidin were found to inhibit the efflux of P-glycoprotein substrate rhodamine 123, in a concentration-dependent manner (77). In animal study, hesperidin was found to enhance the bioavailability of diltiazem likely due to increased intestinal absorption and reduced the first-pass metabolism of diltiazem in the intestine and in the liver via an inhibition of cytochrome P450 3A or P-glycoprotein (29). Radioprotective drugsRadioprotective drugs: In animal study, hesperidin exerted radioprotective effects against gamma irradiation (78; 79). SedativesSedatives: In animal study, hesperidin has displayed sedative effects and synergistic effects with sedative agents like benzodiazepines (26; 25). Hesperidin/Herb/Supplement Interactions:
AnalgesicsAnalgesics: In animal study, the sedative action of hesperidin appeared to be mediated, in part, by an opioid mechanism which makes combined use beneficial for not only sedation but also pain management (26). AntacidsAntacids: In clinical study using hesperidin combination products, acidity, dyspepsia, epigastralgia, gastralgia, gastritis, and nausea have been reported (34; 35; 36; 37; 32; 38; 33). AntibacterialsAntibacterials: In laboratory study, hesperidin was found to have antibacterial activity against methicillin-sensitive and methicillin-resistant Staphylococcus aureus isolates (48). Anticoagulants and antiplateletsAnticoagulants and antiplatelets: In vitro, hesperidin has been found to inhibit platelet aggregation by inhibiting PLC-gamma2 phosphorylation and cyclooxygenase-1 activity (16). AnticonvulsantsAnticonvulsants: In vitro, hesperidin antagonized the effects of 4-aminopyridine (4-AP) and bicuculline (22). AntihistaminesAntihistamines: In vitro, 50% methanol extract of Citrus unshiu exerted inhibitory activity against histamine release from basophils of human subjects (49). Anti inflammatory herbsAnti inflammatory herbs: In animal study, hesperidin produced limited anti-inflammatory effects in rats with experimental arthritis (50). In vitro, it has been speculated that hesperidin may inhibit cyclooxygenase (COX) 2 (51). In animal study, synergistic effects were noted with the combined use of neohesperidin or hesperidin and an anti-inflammatory (52; 53). AntilipemicsAntilipemics: In human study, Daflon?, a hesperidin-containing product, has been found to lower total cholesterol, LDL-cholesterol and triglycerides (18). In animal study, hesperidin has been found to lower plasma and hepatic triglyceride and cholesterol levels (19; 20; 21). AntineoplasticsAntineoplastics: In vitro, hesperidin demonstrated anticarcinogenic effects (51; 54; 55; 56; 57; 58; 59; 60; 61; 62). In mice bone marrow cells, hesperidin protected against cyclophosphamide-induced genotoxicity through antioxidant mechanisms (63). Hesperidin is an active ingredient in the Japanese herbal combination product, rikkunshito. Rikkunshito also consists of eight herbs. Coadministration of rikkunshito and a 5-HT2C receptor antagonist (SB242084HCl) resulted in suppressed cisplatin-induced anorexia by inhibiting growth hormone secretagogue receptor 1a (GHS-R1a) mRNA signal transduction in the hypothalamus (64); the effects of hesperidin alone, however, are unclear using this combination. AntiviralsAntivirals: Hesperidin protected against the action of influenza virus in HeLa cells (65). AnxiolyticsAnxiolytics: In animal study, hesperidin has displayed sedative effects and synergistic effects with anxiolytics (26; 25). CalciumCalcium: In animal study, hesperidin added to the diet prevented decreases in concentration of calcium in the femur (20). Cardiovascular herbs and supplementsCardiovascular herbs and supplements: Hesperidin exerted antiatherogenic effects in vitro (23). In human umbilical vein endothelial cells, hesperidin inhibited strain-induced endothelin-1 secretion, increased the formation of reactive oxygen species, and extracellular signal-regulated kinase (ERK) phosphorylation (24). In human study, Cirkan, containing Ruscus aculeatus (plant extract), hesperidine methylchalcone (flavonoid) and vitamin C, was found to decrease capillary limb diameter and improve capillary morphology (66). Cytochrome P450 metabolized herbs and supplementsCytochrome P450 metabolized herbs and supplements: Hesperidin, which has a lower level of furanocoumarins compared to other flavonoids, displayed weak inhibitory effects against cytochrome P450 2C9, 2D6, and 3A4 in vitro (31). In animal study, hesperidin was found to inhibit cytochrome P450 3A or P-glycoprotein (29). Dental and periodontal agentsDental and periodontal agents: In vitro, a hesperidin-loaded microemulsion enhanced permeation compared to the aqueous and isopropyl myristate suspension; in in vivo study, the hesperidin-loaded microemulsion displayed topical whitening effects and diminished skin irritation compared to the non-treatment group (67). Gastrointestinal herbs and supplementsGastrointestinal herbs and supplements: The combination of Fructus aurantii Immaturus and Radix Paeoniae alba has been used for gastrointestinal disorders and has displayed bilateral effects. Hesperidin and synephrine are constituents found in this combination. Hesperidin has been found to stimulate gastrointestinal movement via histamine (H1) receptor while synephrine has been found to inhibit through the alpha-adrenergic receptor. In animal study, the bilateral effect of this combination was found to occur through regulation on NF-kappa B p65 translocation and NO production through alpha-adrenergic receptor and H1 receptor (70). Hepatotoxic herbs and supplementsHepatotoxic herbs and supplements: In animal study, hesperidin has demonstrated hepatoprotective effects in the liver (71; 72; 73). HypoglycemicsHypoglycemics: In human study, Daflon?, a hesperidin-containing product, has been found to lower blood glucose (18). In animal study, hesperidin prevented hyperglycemia and reduced blood glucose, in part, by increasing hepatic glycolysis and glycogen concentration or by lowering hepatic gluconeogenesis (21; 27). It was also found to increase hepatic glucokinase activity, reduce hepatic glucose transporter 2 protein expression, and elevate the expression of adipocyte glucose transporter 4 and hepatic and adipocyte peroxisome proliferator-activated receptor gamma in animal study,(19; 27; 21). HypotensivesHypotensives: In animal study, glucosyl hesperidin enhanced endothelium-dependent vasodilation in response to acetylcholine and reduced oxidative stress (17). Nephrototoxic herbs and supplementsNephrototoxic herbs and supplements: In animal study, hesperidin produced protective effects in the kidney against sodium arsenite toxicity (decreases in vacuolation of tubular epithelium, interstitial blood) (72), and carbon tetrachloride's effects (75). Neurologic herbs and supplementsNeurologic herbs and supplements: In laboratory study, hesperidin and neohesperidin protected against H2O2-induced cytotoxicity in PC12 cells (76). NicotineNicotine: In rats, hesperidin decreased nicotine's increase in matrix metalloproteinases' total activity and depletion of the activity or concentration of antioxidants (80). Osteoporosis herbs and supplementsOsteoporosis herbs and supplements: In animal study, hesperidin demonstrated beneficial effects on bone (68; 69; 20). P-glycoprotein modulatorsP-glycoprotein modulators: In human colon and leukemia cell lines, hesperidin and neohesperidin were found to inhibit the efflux of P-glycoprotein substrate rhodamine 123, in a concentration-dependent manner (77). In animal study, hesperidin was found to inhibit cytochrome P450 3A or P-glycoprotein (29). Radioprotective agentsRadioprotective agents: In animal study, hesperidin exerted radioprotective effects against gamma irradiation (78; 79). Ruscus aculeatusRuscus aculeatus: In human study, Cirkan, a venotonic drug containing Ruscus aculeatus (plant extract), hesperidine methylchalcone (flavonoid) and vitamin C, was found to decrease capillary limb diameter and improve capillary morphology (66). SedativesSedatives: In animal study, hesperidin has displayed sedative effects and synergistic effects with sedatives (26; 25). SunscreenSunscreen: Padimate O, a sunscreen agent, was found to increase the permeation rate of hesperidin (67). ValerianValerian: In animal study, hesperidin has displayed sedative effects and synergistic effects with sedative agents (26; 25). VanadylVanadyl: In animal study, vanadyl (IV) cation and hesperidin were found to improve the superoxide dismutase (SOD)-like activity, stimulate cell proliferation and collagen type I production at low concentrations on the osteoblastic cell line, and behave as a cytotoxic compound for osteoblasts at high concentrations (81). Vitamin CVitamin C: In human study, Cirkan, containing Ruscus aculeatus (plant extract), hesperidine methylchalcone (flavonoid) and vitamin C, was found to decrease capillary limb diameter and improve capillary morphology (66). Hesperidin/Food Interactions:
Calcium-containing foodsCalcium-containing foods: In animal study, hesperidin added to the diet may prevent decreases in concentration of calcium in the femur (20). Vitamin C-containing foodsVitamin C-containing foods: In human study, Cirkan, containing Ruscus aculeatus (plant extract), hesperidine methylchalcone (flavonoid) and vitamin C, was found to decrease capillary limb diameter and improve capillary morphology (66). YogurtYogurt: In human study, consumption of yogurt with orange juice (which contains hesperidin) resulted in reduced excretion of phenolic acids including hesperidin-7-O-rutinoside (82). Hesperidin/Lab Interactions:
Blood glucoseBlood glucose: In human and animal study, hesperidin and hesperidin-containing products have been found to reduce blood glucose (18; 21; 27). Blood glutathioneBlood glutathione: In human study, Daflon?, a hesperidin-containing product, was found to increase levels of blood glutathione in patients with type 2 diabetes (18).Blood pressureBlood pressure: In animal study, glucosyl hesperidin enhanced endothelium-dependent vasodilation in response to acetylcholine and reduced oxidative stress by inhibiting nicotinamide adenine dinucleotide phosphate oxidase expression in the vasculature, thereby improving hypertension in spontaneously hypertensive rats (17). Coagulation panelCoagulation panel: In vitro, hesperidin has been found to inhibit platelet aggregation by inhibiting PLC-gamma2 phosphorylation and cyclooxygenase-1 activity (16). C-reactive proteinC-reactive protein: In human study, Daflon?, a hesperidin-containing product, was found to lower C-reactive protein in patients with type 2 diabetes (18).Lipid profileLipid profile: In human and animal study, hesperidin and hesperidin-containing products have been found to lower total cholesterol, LDL cholesterol, and triglycerides (19; 20; 21; 18). MalondialdehydesMalondialdehydes: In human study, Daflon?, a hesperidin-containing product, was found to lower malondialdehydes (an index of lipid peroxidation) in patients with type 2 diabetes (18).Nitric oxide levelsNitric oxide levels: In human study, Daflon?, a hesperidin-containing product, was found to increase levels of nitric oxide in patients with type 2 diabetes (18).RadiotherapyRadiotherapy: In the micronucleus test in bone marrow of mice, hesperidin decreased cytotoxicity of gamma rays, as well as their effect as a clastogen, although at above the most effective dose, clastogenic action occurred (79). Serum calciumSerum calcium: In animal study, hesperidin added to the diet prevented decreases in concentration of calcium in the femur (20). Viral loadViral load: Hesperidin has been shown to protect against the action of influenza virus in HeLa cells (65).