We developed a naringenin–hesperidin molar mixture (MIX–160) with proven antihyperglycemic and vasorelaxant activity in preclinical studies. A solid dosage form was manufactured to improve the bioavailability properties. In the current study, we sought to evaluate the oral preclinical toxicity of the MIX–160 dosage form, which showed no mortality or significant changes in the body weight, food consumption and tissue/organ mass in rats. Three daily oral doses (50, 300 and 2000 mg/kg of MIX–160) were assayed for 28 days. The results showed no structural abnormalities in the histological analysis and no significant changes (p > 0.05) in the liver biochemical markers (total bilirubin, AST and ALT) compared to the control group. The above findings showed that the MIX–160 dosage form did not exhibit relevant toxic effects, which suggests its potential safety as a drug candidate for clinical studies.

This study was performed to evaluate and compare the pharmacokinetic parameters between two dosage formulations of hesperidin and naringenin: mixture and tablet. Our objective was to determine that the flavonoid tablet does not significantly modify the pharmacokinetic parameters compared with the mixture. For this study, we administered 161 mg/kg of either mixture (Mix-160) or tablet composed of hesperidin and by intragastric administration. Blood microsamples were collected from tail vein up to 24 h. Serum flavonoid extraction was performed by solid phase extraction and analyzed by LC-MS/MS of triple quadrupole (QqQ). Serum concentration vs. time plot showed that data fitted for a first-order model. The pharmacokinetic parameters were calculated by a noncompartmental model. The results showed that the absorption constant is higher than the elimination constant. The first concentration was found at five minutes, and minimal concentration at 24 h after administration, suggesting a enterohepatic recirculation phenomena and regulation of liver cytochromes’ activity. We did not find meaningful differences between the pharmacokinetic parameters of both samples. We concluded that tablet form did not interfere with the bioavailability of hesperidin and naringenin, and it could be a suitable candidate for developing a drug product.

Flavonoids are naturally occurring compounds widely distributed in the Citrus genus. These natural compounds have many health benefits, mainly for metabolic and cardiovascular diseases. In fact, some these compounds are components of drug products with approved indications for peripheral vascular insufficiency and hemorrhoids. However, information on pharmacological effects of these compounds remains disperse and there is scarce comprehensive analysis of whole data and evidence. These kinds of evidence analyses could be necessary in drug design and the development of novel and innovate drug products in diabetes and hypertension. We aimed to systematically search for evidence on the efficacy of citroflavonoids in diabetes and hypertension in in vivo models. We searched four literature databases based on a PICO strategy. After database curation, twenty-nine articles were retrieved to analyze experimental data. There was high heterogeneity in both outcomes and methodology. Naringenin and hesperetin derivates were the most studied citroflavonoids in both experimental models. More investigation is still needed to determine its potential for drug design and development.

Diabetes is one of the most prevalent diseases worldwide, and the search for therapeutic alternatives in developing countries has been focused on natural products, primarily from plants. This study evaluated the antihyperglycemic and hypoglycemic activities of the albedo (FA) and flavedo (FF) flavonoid fractions obtained from orange peels (often discarded) in normoglycemic Wistar rats. The flavonoid fractions were identified and quantified using HPLC-UV-DAD and compared with glibenclamide, repaglinide, saxagliptin, and acarbose. Additionally, both fractions were tested in a streptozotocin (65 mg/kg)/nicotinamide (100 mg/kg)-induced diabetic model. In normoglycemic rats, the highest glucose variation (%VG) occurred during the first hour after FA (112.8%) and FF (105.30%) administration at 100 mg/kg, indicating a hypoglycemic effect. In diabetic rats, FF at 100 mg/kg showed the highest %VG (140.41%) during the first hour after administration. HPLC-UV-DAD analysis revealed the presence of hesperidin (HSP) and naringenin (NGN), with the highest concentrations found in FA (HSP: 41.41%; NGN: 10.75%). These findings suggest potential antihyperglycemic effects of FA and FF fractions, possibly attributed to the presence of HSP and NGN. The results obtained in this work lay the foundations to explore the therapeutic applications of orange peels for controlling hyperglycemia in diabetes. In conclusion, our results suggest a reevaluation and revalorization of orange peels, as they contain pharmaceutically relevant flavonoids.