Pharmacokinetic-Pharmacodynamic Modeling of the Antioxidant Activity of Quzhou Fructus Aurantii Decoction in a Rat Model of Hyperlipidemia

• Published in: Biomedicine & pharmacotherapy Vol. 131; p. 110646
• Main Authors: Ying, Yuqi, Wan, Haoyu, Zhao, Xixi, Yu, Li, He, Yu, Jin, Weifeng
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.11.2020; Elsevier
• Subjects: Animals; Antioxidants - administration & dosage; Antioxidants - pharmacokinetics; correlation; Diet, High-Fat - adverse effects; Disease Models, Animal; Drugs, Chinese Herbal - administration & dosage; Drugs, Chinese Herbal - pharmacokinetics; hyperlipidemia model; Hyperlipidemias - drug therapy; Hyperlipidemias - etiology; Hyperlipidemias - metabolism; luteolin; Male; neohesperidin; nobiletin; oxidation; pharmacokinetic-pharmacodynamic; Quzhou Fructus Aurantii; Rats; Rats, Sprague-Dawley; Rutaceae; luteolin; nobiletin; correlation; oxidation; neohesperidin; pharmacokinetic-pharmacodynamic; Quzhou Fructus Aurantii; hyperlipidemia model
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.110646

[Display omitted] •QFA decoction PK and PD in hyperlipidemia and normal rats was studied.•QFA decoction shows antioxidant activity in the hyperlipidemia rats.•PK-PD model was achieved by a three-compartment PK model with sigmoid  Emax PD model.•Constructed model provided fundamental data for further study on applications of QFA.•Deeper studies help better inspect the pathogenesis of hyperlipidemia. Quzhou Fructus Aurantii (QFA) is an herb that is commonly used to alleviate inflammation in individuals dealing with obesity.To date, however, no systematic pharmacokinetic (PK) or pharmacodynamic (PD) analyses of the clinical efficacy of QFA under hyperlipemia-associated oxidative stress conditions have been conducted. The present study, was therefore designed to construct a PK-PD model for this herb, with the goal of linking QFA PK profiles to key therapeutic outlines to guide the therapeutic use of this herb in clinical settings. Rats were fed a high-fat diet in order to establish a model of hyperlipidemia, after which they were randomized into a normal control group (NCG), a normal treatment group (NTG), a model control group (MCG), and a model treated group (MTG) (n = 6 each). QAF decoction was used to treat rats in the NTG and MTG groups (25 g/kg), while equivalent volumes of physiological saline were administered to rats in the NCG and MCG groups. Plasma samples were collected from the mandibular vein for animals at appropriate time points and analyzed via high-performance liquid chromatography (HPLC). We evaluated PK properties for three QAF components and compared these dynamics between the NTG and MTG groups, while also measuring levels of lipid peroxidation (LPO) in the plasma of rats in all four treatment groups. We then constructed a PK-PD model based upon plasma neohesperidin, luteolin, and nobiletin concentrations and LPO levels using a three-compartment PK model together with a Sigmoid Emax PD model. This model thereby enabled us to assess the antioxidative impact of neohesperidin, luteolin, and nobiletin on hyperlipidemia in rats. When comparing the NTG and MTG groups, we detected significant differences in the following parameters pertaining to neohesperidin, luteolin, and nobiletin:t1/2β, V1,  t1/2γ, CL1 (p < 0.01) and AUC0-t, Tmax, Cmax (p < 0.05). Relative to NTG group rats, AUC0-t, TmaxandCmaxvalues significantly higher for MTG group rats (p < 0.01), while t1/2β, V1, and  t1/2γ values were significantly lower in MTG group rats (p < 0.01) in MTG rats. QAF decoction also exhibited excellent PD efficacy in MTG rats, with significant reductions in plasma LPO levels relative to NTG rats (p < 0.01) following treatment. This therapeutic efficacy may be attributable to the activity of neohesperidin, luteolin, and nobiletin, as LPO levels and plasma concentrations of these compounds were negatively correlated in treated rats. Based upon Akaike Information Criterion (AIC) values, we determined that neohesperidin, luteolin, and nobiletin PK processes were consistent with a three-compartment model. Together, these findings indicated that three active components in QAF decoction (neohesperidin, luteolin, and nobiletin) may exhibit antioxidant activity in vivo. Our in vivo data indicated that neohesperidin, luteolin and nobiletin components of QAF decoctions exhibit distinct PK and PD properties. Together, these findings suggest that hyperlipidemia-related oxidative stress can significantly impact QFA decoction PK and PD parameters. Our data additionally offer fundamental insights that can be used to design appropriate dosing regimens for individualized clinical QAF decoction treatment.