Effects of acute renal failure induced by uranyl nitrate on the pharmacokinetics of liquiritigenin and its two glucuronides, M1 and M2, in rats.

OBJECTIVES: Liver disease and acute renal failure (ARF) are closely associated. The pharmacokinetics of liquiritigenin (LQ), a candidate therapy for inflammatory liver disease, and its metabolites M1 and M2 were evaluated in rats with ARF induced by uranyl nitrate (U-ARF rats). METHODS: LQ was administered intravenously (20 mg/kg) or orally (50 mg/kg) in U-ARF and control rats, and uridine diphosphate-glucuronosyltransferases (UGT) activity and uridine 5'-diphosphoglucuronic acid (UDPGA) concentrations were determined in the liver and intestine. KEY FINDINGS: After intravenous LQ administration, U-ARF rats displayed significantly slower LQ renal clearance but no significant changes in the LQ area under the plasma concentration-time curve (AUC) compared with controls. This was because of similar hepatic UGT activity and UDPGA levels between two groups, which resulted in comparable non-renal clearance, as well as the limited contribution of LQ renal clearance to total LQ clearance. However, the AUC and AUC(M) /AUC(LQ) ratios of M1 and M2 were significantly increased in U-ARF rats because of decreased urinary excretion of M1 and M2. Similar results were observed following oral administration because of the comparable LQ intestinal metabolism in both groups and decreased urinary excretion of M1 and M2 in U-ARF rats. CONCLUSIONS: U-ARF rats displayed decreased urinary excretion of LQ glucuronides, resulting in significantly greater AUC and metabolite ratios of M1 and M2 following LQ administration.

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.

Pharmacokinetics of liquiritigenin in mice, rats, rabbits, and dogs, and animal scale-up.

Pharmacokinetics of liquiritigenin (LQ) and its two glucuronide metabolites, M1 and M2, in mice, rats, rabbits, and dogs and animal scale-up of the pharmacokinetic parameters of LQ were evaluated. After intravenous administration of LQ, the AUC (AUC(0-t)) values of LQ, M1, and M2 were proportional to LQ doses in all animals studied. Animal scale-up of some pharmacokinetic parameters of LQ was performed based on the parameters after its intravenous administration (20 mg/kg; in the linear pharmacokinetic range) to the four species. Linear relationships were obtained (r > 0.968) between log CL (or CL/f(u)) (L/h) and log species body weight (W) (kg) [CL (or CL/f(u)) = 3.29 (34.0) W(0.723 (0.789))] and log V(ss) (or V(ss)/f(u)) (L) and log W (kg) [V(ss) (or V(ss)/f(u)) = 0.340 (3.52) W(0.882 (0.948))]. Interspecies scale-up of plasma concentration-time data of LQ using apolysichron (complex Dedrick plots) resulted in similar profiles, and plasma concentration-time profile of humans were predicted using the well-fitted four animal data. Our results indicate that the LQ data obtained from laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters of LQ in humans. These parameters can serve as guidelines for better planning of clinical studies.