Abstract
Neohesperidin, the most abundant compound found in the flowers of Citrus aurantium L. var. amara Engl., has shown a significant therapeutic effect on obesity caused by a high sugar diet. Nevertheless, the pharmacokinetic differences of neohesperidin between lean and obese rats have not been evaluated, which is crucial information for its clinical application in treating obesity. In this study, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was established to explore the pharmacokinetic differences of oral administration (100 mg/kg) and intravenous injection (4 mg/kg) of neohesperidin in lean and obese rats. The absolute oral bioavailability of total neohesperidin in lean and obese rats was approximately 5.30% and 4.03%, respectively, with no significant statistical difference (p > 0.05). Compared to lean rats, obese rats exhibit higher levels of urinary and fecal excretion of total neohesperidin and its metabolite total hesperetin within 48 h following oral administration, whereas total luteolin has the opposite effect. The excretion of neohesperidin in the urine was primarily in the form of its metabolite hesperetin, whereas in the feces, it was measured both as neohesperidin and as hesperetin. Furthermore, experiments involving the continuous gavage of neohesperidin for 15 days have confirmed that obese rats possess superior excretion capabilities for neohesperidin compared to lean rats. Our findings suggest that there are distinct differences in the excretion of neohesperidin between obese and lean rats. However, the precise causes of these differences require further investigation in the future, which may be related to gut microbiota and liver metabolic enzymes.