The protective effect of rutin against lipopolysaccharide induced acute lung injury in mice based on the pharmacokinetic and pharmacodynamic combination model

Rutin is a flavonoid compound with many pharmacological activities, including antioxidation, anti-inflammation and cardiovascular and cerebrovascular protection. However, there are great limitations in clinical application in view of its poor solubility and slow absorption in vivo. In this study, a pharmacokinetic and pharmacodynomic model was adopted to study the correlation of the pharmacokinetics and pharmacodynomics of rutin in lipopolysaccharide-induced acute lung injury mice. Rutin was intragastrically administered continuously for 5 days at a dose of 200 mg/kg/d, and pharmacokinetic and pharmacodynamic indicators were measured every day after administration, including the blood concentration of rutin, the W/D ratio of lungs, the nitric oxide content and the expression levels of TLR4, TRAF6, IκB and P-IκB proteins. The results indicated that rutin can exert an anti-inflammatory protective effect by improving lung tissue injury, significantly decreasing the synthesis of the inflammatory mediator nitric oxide, and inhibiting the protein expression levels of TLR4, TRAF6 and P-IκB. The absorption of rutin conformed to a one-compartment model with the pharmacokinetic parameters as follows: t1/2α= 9.76 h, t1/2β= 19.44 h, Tmax= 24.00 h, Cmax= 22.65 μg/ml and AUC(0-t)= 518.58 μg/ml·h. A PK-PD combination model was established to fit the optimal administration time of rutin with a one-compartment-Sigmod Emax model connected to the effect site. Meanwhile,the PK-PD combination model was a better approach for evaluating the relationships between the five pharmacodynamic indicators and the pharmacokinetic characteristics of rutin. The correlation between the pharmacokinetics and pharmacodynamics of rutin was quantitatively analysed to provide a theoretical basis for the research and development of new anti-inflammatory drugs in clinical practice.