Changes of pharmacokinetics of 6,7-dimethoxycoumarin in a rat model of alpha-naphthylisothiocyanate-induced experimental hepatic injury after Yinchenhao Decoction (茵陈蒿汤) treatment

Abstract

To study the changes of pharmacokinetics of 6,7-dimethoxycoumarin in a rat model of alpha-naphthylisothiocyanate (ANIT)-induced experimental hepatic injury after oral administration of Yinchenhao Decoction (, YCHD) using an ultra pressure liquid chromatography (UPLC) method. Rats were divided into a normal group and a model group, after modeled by 4% ANIT (75 mg/kg) for 48 h, they were orally administrated with YCHD extract at the dose of 0.324 g/kg, and then blood was collected from their orbital sinus after different intervals. Changes in liver function were monitored by the levels of liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST)] and bilirubins [total bilirubin (TBIL), direct bilirubin (DBIL)], the concentration of 6,7-dimethoxycoumarin in plasma were measured by UPLC, and the pharmaceutical parameters were calculated with DAS2.1.1 software. The concentration-time curve of both normal and modeled rats after oral administration of YCHD was obtained. Their time to maximum plasma concentration (t(max)) were both 0.25 h, the maximum concentration (C(max)) were 4.533 μg/mL and 6.885 μg/mL, and their area under concentration-time curve (AUC)(0→24h) were 16.272 and 32.981, respectively. There was a 51.88% and 100.46% increase in C(max) and AUC(0-t) (P<0.05), but there showed a 45.52% and 92.93% reduction in clearance of drug and volum of distribution (P<0.05), respectively. Hepatic injury could significantly influence the pharmacokinetics of 6,7-dimethoxycoumarin after oral administration of YCHD, the absorption and distribution process was accelerated in liver injured rats, but the metabolism and elimination process was slowed. And this may lead to a significant accumulation of 6,7-dimethoxycoumarin in the body.