Liquiritigenin pharmacokinetics in a rat model of diabetes mellitus induced by streptozotocin: greater formation of glucuronides in the liver, especially M2, due to increased hepatic uridine 5′-diphosphoglucuronic acid level

Liquiritigenin (LQ) is a candidate for the treatment of inflammatory liver disease. Many studies have confirmed that hepatic disease and diabetes mellitus are closely associated. Thus, the pharmacokinetic changes of LQ and its 2 glucuronides, M1 and M2, in a rat model of diabetes mellitus induced by streptozotocin (DMIS rats) were evaluated. Liquiritigenin was administered intravenously (20 mg/kg) or orally (50 mg/kg) in DMIS and control rats. Changes in in vitro activity and in vivo uridine 5'-diphosphoglucuronic acid level in the liver and intestine of DMIS rats compared with controls were also studied. After intravenous administration of LQ in DMIS rats, no significant changes in the pharmacokinetic parameters of LQ were observed. However, the AUC(M2)/AUC(LQ) ratio was significantly greater (by 53.0%) than that of controls. After oral administration of LQ, the AUC of LQ and metabolite ratios of M1 and M2 were comparable to controls. The increase in the formation of glucuronides of LQ, especially M2, after intravenous administration of LQ was due to the increased in vivo hepatic uridine 5'-diphosphoglucuronic acid level in DMIS rats as a result of alteration in carbohydrate metabolism in diabetes. The comparable pharmacokinetics of LQ, M1, and M2 after oral administration of LQ were mainly due to the comparable intestinal metabolism of LQ between the control and DMIS rats.