Pharmacokinetic/Pharmacodynamic Modeling Of Antipyretic And Anti-inflammation Of Rhubarb In The Rat

ObjectiveThe purpose of this research is to explore the effect of rhubarb on antipyretic and anti-inflammatory in different stages of the inflammatory response. The pharmacokinetic difference induced by the time of injecting lipopolysaccharide was also explored in rats. The potency, efficacy and dose-effect relationship of Rhubarb and Rhein for reducing temperature and the concentration of NO and the contribution of microscopic mechanism to the macro effect were evaluated quantificationally by PK-PD model.MethodsThe concentration of rhein in rhubarb was detected by HPLC-FLD. The rats in model group were injected LPS to induce inflammation. The rats of rhein and rhubarb group were received rhein solution and rhubarb decoction by gastric perfusion after injecting LPS for0.5or2hours, respectively. The value of body temperature (BT) was recorded and the blood samples were collected at different time points after. The effect of rhein and rhubarb on inflammation was compared through the level of BT and NO in plasma. The change on pharmacodynamics of rhubarb induced by LPS and modeling at different time was analyzed though pharmacokinetic parameters. Relevant data of PK-PD modeling were performed with Kinetica software to evaluate the effect of rhein and rhubarb on reducing BT and the concentration of NO in plasma in inflammatory model rats.Results(1)The content for Rhein was5mg/g. Rhubarb decoction can inhibit the BT at0.5h and2h. BT can be suppressed by Rhein in0.5h group, but2h group has no effect. Rhein and rhubarb decoction both can inhibit the increase NO concentration in plasma of0.5h group, but2h group has no effect. The effect of Rhubarb decoction suppressing the temperature is stronger than Rhein both0.5h and2h group. NO inhibition effect of Rhein is about2times of rhubarb decoction in0.5h group.(2)The parameters, for instance t1/2, Cmax, AUC, for LPS increased, compared to those for normal saline. The parameters, for instance Cmax, AUC, for2h group increased, t1/2and MRT decreased, compared to the0.5group.(3)The effect of body temperature and NO concentration inhibition are strengthened by administration Rhubarb decoction and Rhein repetitive after the interval4hours.(4)The antipyretic and anti-inflammatory responses were best described by an Sigmod EMAX model. Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains. The two values of EC50of Rhubarb decoction were114.1ng/ml and90.80ng/ml.The estimating Emax of antipyretic is close to111%of the BT changes, and is very much greater than the Emax value of anti-inflammatory (8.399%). The two values of EC50of Rhein were5.885and5.458ng/ml. The estimating Emax of antipyretic is close to56.77%of the BT changes, and is very much greater than the Emax value of anti-inflammatory (25.85%). The value of EC50of the BT changes of Rhubarb decoction and Rhein were202.2and104.3ng/ml. Emax were0.84and0.76℃.ConclusionThe pharmacokinetic process of Rhein after normal saline and LPS are different. The targets of regulating NO production and BT after administration rhubarb may be at the same location. Antipyretic effect induced by rhubarb maybe not completely work through reducing the plasma concentration of NO.