Pharmacokinetics of liquiritigenin and its two glucuronides, M1 and M2, in rats with acute hepatitis induced byd-galactosamine/lipopolysaccharide or CCl₄

Abstract

Cytoprotective effects of liquiritigenin (LQ) against liver injuries have been reported, but its pharmacokinetics has not been studied in acute hepatitis. Thus, pharmacokinetics of LQ and its two conjugated glucuronide metabolites: 4'-O-glucuronide (M1) and 7-O-glucuronide (M2), in rats with acute hepatitis induced by d-galactosamine/lipopolysaccharide (GalN/LPS) rats or carbon tetrachloride-treated (CCl(4)-treated) rats were evaluated. LQ was administered intravenously (20 mg kg(-1)) and orally (50 mg kg(-1)) to control GalN/LPS and CCl(4)-treated rats. Expression of uridine 5'-diphospho-glucuronosyltransferases 1A (UGT1A) and in vitro metabolism of LQ in hepatic and intestinal microsomes were also measured. After intravenous administration of LQ, area under the plasma concentration-time curve (AUC) of LQ in GalN/LPS rats was significantly smaller than that in controls due to faster non-renal clearance, as a result of its greater free fraction in plasma and faster hepatic blood flow rate than the controls. In CCl(4)-treated rats, the AUC(M1, 0-8 h)/AUC(LQ) and AUC(M2, 0-8 h)/AUC(LQ) ratios were significantly greater than the controls due to decrease in biliary excretion of M1 and M2. However, no significant pharmacokinetic changes were observed in both acute hepatitis rats after oral administration due to comparable intestinal metabolism of LQ. Modification of oral dosage regimen of LQ may not be necessary in patients with acute hepatitis; but human studies are required.

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

“…Male Sprague‐Dawley rats (8–10 weeks old, 260–325 g) were purchased from Charles River Company Korea (Seoul, South Korea). Animal housing and maintenance were similar to those in previous studies [6–10] …”

“…The procedures used for the measurement of maximum velocity ( V max ) and the apparent Michaelis–Menten constant ( K m ) for the disappearance of LQ and the formation of M1 and M2 were similar to previously reported methods [8–10,25] . Microsomes (0.1 and 0.2 mg total protein for hepatic and intestinal microsomes, respectively), 0.1 m Tris‐HCl buffer (pH 7.4), 1 m m MgCl 2 in Tris‐HCl (pH 7.4), and alamethicin (dissolved in 50% ethanol; 50 µ g/mg protein) were mixed and placed on ice for 10 min.…”

“…Cannulation of the carotid artery (for blood sampling) and the jugular vein (for drug administration in the intravenous study) was performed as in previous studies [6–10] . Rats were allowed to recover from light ether anaesthesia for 4–5 h before the study began, and were not restrained during drug administration or blood collection.…”

“…A recent report examined the pharmacokinetics of LQ, M1 and M2 after intravenous and/or oral administration of various doses of LQ to four species (mice, rats, rabbits and dogs) and used these animal data to predict human LQ pharmacokinetics [7] . The effects of co‐administered dimethyl‐4,4′‐dimethoxy‐5,6,5′,6′‐dimethylenedioxybiphenyl‐2,2′‐dicarboxylate, a synthetic hepatoprotective agent derived from schizandrin C, [8] acute hepatitis induced by d ‐galactosamine/lipopolysaccharide or carbon tetrachloride, [9] and diabetes mellitus induced by streptozotocin [10] on the pharmacokinetics of LQ, M1 and M2 in rats have also been reported.…”

Chiral analytical method development of liquiritigenin with application to a pharmacokinetic study

“…The pharmacokinetics of racemic liquiritigenin via achiral high‐performance liquid chromatography (HPLC) methods has been studied extensively (Li et al ., ; Kang et al ., , , , ). However, chirality is an aspect often overlooked in the pharmacometric characterization of phytochemicals, including flavonoids.…”