High body clearance and low oral bioavailability of alantolactone, isolated from Inula helenium, in rats: extensive hepatic metabolism and low stability in gastrointestinal fluids

ABSTRACT Alantolactone (ALA) is a major bioactive sesquiterpene lactone present in the roots of Inula helenium L. (Asteraceae) which has been widely used in traditional medicine against various diseases such as asthma, cancer, and tuberculosis. Pharmacologic activities of ALA have been well characterized, yet information on the physicochemical and pharmacokinetic properties of ALA and their mechanistic elucidation are still limited. Thus, this study aims to investigate the oral absorption and disposition of ALA and their relevant mechanisms. Log P values of ALA ranged from 1.52 to 1.84, and ALA was unstable in biological samples such as plasma, urine, bile, RLM, and simulated gastrointestinal fluids. The metabolic rate of ALA was markedly higher in rat liver homogenates than the other tissue homogenates. A saturable and concentration‐dependent metabolic rate profile of ALA was observed in RLM, and rat cytochrome P450 (CYP) 1A, 2C, 2D, and 3A subfamilies were significantly involved in its hepatic metabolism. Based on the well‐stirred model, the hepatic extraction ratio (HER) was estimated to be 0.890–0.933 classifying ALA as drug with high HER. Moreover, high total body clearance (111 ± 41 ml/min/kg) and low oral bioavailability (0.323%) of ALA were observed in rats. Taken together, the present study demonstrates that the extensive hepatic metabolism at least partially mediated by CYP is primarily responsible for the high total body clearance of ALA, and that the ...
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: Original Paper Source Type: research