Population Pharmacokinetics Of Rhubarb In Rats With Chronic Renal Failure Or Acute Liver Injury

ObjectiveThe purpose of the present study was to evaluate the influence of biochemical markers of liver and renal function on population pharmacokinetic parameters of rhubarb by a NONMEM method and investigate the pharmacokinetic characteristics of rhein in rats with chronic renal failure or acute liver injury. In particular, we wanted to investigate whether there was a causal relationship between the efficacy or toxicity of rhubarb and the pharmacokinetic characteristics of rhein under different physiological or pathological states in rats.MethodsFirst of all, the contents of free anthraquinones in rhubarb were determined according to the Pharmacopoeia of the People’s Republic of China (2010Edition). Then, the stability of5FRAs in the water extract of rhubarb was investigated and the method for the determination of rhein in rat’s plasma by HPLC-FLD was established. The chronic renal failure model was induced by adenine and the acute hepatic injury model was established by D-GalN. Furthermore, the biochemical indicators and the pharmacokinetic data were collected. Finally, the pharmacokinetic parameters were calculated by Kinetica5.0software. In addition, we established the final regression model for rhein and evaluated the influence of weight, sex and the biochemical indicators on the population pharmacokinetic parameters of rhein in rats.Results(1)The content of total free anthraquinones was2.09%. The content of aloe-emodin, rhein, emodin, chrysophanol and physcion in rhubarb decoction didn’t have significant difference when stored at4℃for30days.(2)A sensitive, convenient, reliable HPLC-FLD detection assay was established for the determination of rhein in rat plasma.(3)Compared with the control group of the same sex, the concentration of Urea and Crea was significantly increased in chronic renal failure model groups. The concentration of TP, ALB was significantly decreased while the TBIL, ALT, AST, ALP levels were significantly increased in acute liver injury model groups.(4) The Cmax and AUC of Rhein in female rats were significantly higher than in male rats at the same physiological and pathological state; Compared with the normal group, the Kel, K12were significantly decreased in chronic renal failure rats.The Kel was significantly increased and the MRT and AUC were significantly decreased in acute liver injury rats. The Sex, AST, Weight has a significant effect on Ka, the final regression model for Ka was:Ka=0.1403+Sexx(-0.04805)+ASTx0.000149+Weightx (-6.301×10-5). The Sex, AST, Crea has a significant effect on Kel, the final regression model for Kel was:Kel=0.0006745+Sex×(-1.5876×10-8)+Creax(-1.609×10-11)+AST×(-6.152×10-12).ConclusionThere are gender-related differences in pharmacokinetics of rhein between male and female rats. Compared with normal animals the pharmacokinetic parameters of rhein were significant differences in chronic renal failure and acute liver injury rats. The Sex, AST, Weight has a significant effect on Ka and the Sex, AST, Crea has a significant effect on Kel. These differences may be one of the most important factors that decided the efficacy or toxicity of rhubarb.