Pharmacokinetics and first-pass effects of liquiritigenin in rats: low bioavailability is primarily due to extensive gastrointestinal first-pass effect

Abstract

Pharmacokinetics of liquiritigenin, a candidate for inflammatory liver disease, and its two glucuronide conjugates, M1 and M2, were evaluated in rats. The hepatic and gastrointestinal first-pass effects of liquiritigenin were also evaluated in rats. After oral administration of liquiritigenin at a dose of 20 mg kg(-1), 1.07% of the dose was not absorbed from the gastrointestinal tract up to 24 h, and the F-value was only 6.68%. In vitro metabolism of liquiritigenin in S9 fractions of rat tissues showed that the liver and intestine were major tissues responsible for glucuronidation of liquiritigenin. The hepatic and gastrointestinal first-pass effects of liquiritigenin were approximately 3.67% and 92.5% of the oral dose, respectively. Although the hepatic first-pass effect of liquiritigenin after absorption into the portal vein was 57.1%, the value was only 3.67% of the oral dose due to extensive gastrointestinal first-pass effect in rats. Therefore, the low F-value of liquiritigenin in rats was primarily attributable to an extensive gastrointestinal first-pass effect although liquiritigenin was well absorbed. Compared with rats, the higher F-value of liquiritigenin could be expected in humans.

Stereospecific pharmacokinetic characterization of liquiritigenin in the rat

“…utilizing intravenous dosing of liquiritigenin 20 mg/kg reported approximate plasma half-lives of 5-8 minutes, clearances of 50-70 mL/min/kg, V ss 240-190 mL/kg, and AUC of 290-410 μg.min/mL. Data from the present study parallel these results with respect to AUC (280-385 μg.min/mL) and clearance (30-50 mL/min/kg) but also demonstrated a comparatively greater half-life (0.25-0.43 h) (2526). The very short half-life of liquiritigenin reported by Kang, et al was calculated utilizing plasma samples only, which may underestimate the actual half-life of liquiritigenin and also emphasizes the importance of utilizing urinary data to calculate pharmacokinetic parameters of liquiritigenin as well as similar flavonoids (2526).…”

“…Data from the present study parallel these results with respect to AUC (280-385 μg.min/mL) and clearance (30-50 mL/min/kg) but also demonstrated a comparatively greater half-life (0.25-0.43 h) (2526). The very short half-life of liquiritigenin reported by Kang, et al was calculated utilizing plasma samples only, which may underestimate the actual half-life of liquiritigenin and also emphasizes the importance of utilizing urinary data to calculate pharmacokinetic parameters of liquiritigenin as well as similar flavonoids (2526). Pharmacokinetic parameters of orally administered liquiritigenin given alone or in a mixture (exact dose unknown) are highly variable between existing studies with approximate plasma half-lives of 3-11 h, and AUC of 19-6594 μg.h/L.…”

“…The bioavailability reported by Kang, et al . was 3-7% after oral doses of 20-50 mg/kg which is lower than the bioavailability reported herein (181921252627). This discrepancy in bioavailability likely results from differences in formulation, fasting state, and vendor supplier of rats and source materials.…”

“…For IV and oral formulations, Kang, et al . dissolved liquiritigenin in a 40:60 ratio of PEG 400: distilled water (2526). These formulations presumably vary greatly from the PEG 600 and DMSO used in these studies which may alter the aqueous solubility and dissolution of liquiritigenin.…”

“…The achiral pharmacokinetics of liquiritigenin, and its corresponding glycosides have been reported in the literature (17). Differences in the disposition of an individual enantiomer may result in significant differences in their health benefits or toxic effects in humans (18192021222324252627). The chiral pharmacokinetics of liquiritigenin have only been preliminarily evaluated by our laboratory and one other group.…”