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 used widely in traditional medicine against various diseases such as asthma, cancer and tuberculosis. The pharmacologic activities of alantolactone have been well characterized, yet information on the physicochemical and pharmacokinetic properties of alantolactone and their mechanistic elucidation are still limited. Thus, this study aims to investigate the oral absorption and disposition of alantolactone and their relevant mechanisms. Log P values of alantolactone ranged from 1.52 to 1.84, and alantolactone was unstable in biological samples such as plasma, urine, bile, rat liver microsomes (RLM) and simulated gastrointestinal fluids. The metabolic rate of alantolactone was markedly higher in rat liver homogenates than in the other tissue homogenates. A saturable and concentration-dependent metabolic rate profile of alantolactone was observed in RLM, and rat cytochrome P450 (CYP) 1 A, 2C, 2D and 3 A 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 alantolactone as a drug with high HER. Moreover, high total body clearance (111 ± 41 ml/min/kg) and low oral bioavailability (0.323%) of alantolactone 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 alantolactone, and that the low oral bioavailability of alantolactone could be attributed to its low stability in gastrointestinal fluids and a hepatic first-pass effect in rats. Copyright © 2016 John Wiley & Sons, Ltd.

Alantolactone, a natural sesquiterpene lactone, has potent antitumor activity against glioblastoma by targeting IKKβ kinase activity and interrupting NF-κB/COX-2-mediated signaling cascades

“…ATL has a rapid onset and does not cause significant damage to normal animal tissues and organs [29, 30]. The antitumor properties of ATL have been demonstrated in peripheral tumors, including lung cancer, liver cancer, colon cancer, and leukemia [31–35].…”

Synergistic lethality between PARP-trapping and alantolactone-induced oxidative DNA damage in homologous recombination-proficient cancer cells

“…These results demonstrated the potential of using nontoxic doses of ATL to produce oxidative DNA damage selectively in cancer cells. Currently, pharmacokinetics (PK) data of ATL in humans are not available, however, studies in rat reported a plasma C max of 1.103 mg/L (4.75 μM) after intravenous administration of Radix Inulae extract containing 3.43 mg/ kg ATL [63] and 0.03 mg/L (0.12 μM) after oral administration at a dose of 50 mg/kg ATL [64]. Our results showed that a significant increase in ROS levels could be induced in cancer cells by an ATL concentration as low as 0.625 μM and strong synthetic lethality was achieved by 1 μM ATL combined with olaparib.…”

Back to the Roots—An Overview of the Chemical Composition and Bioactivity of Selected Root-Essential Oils

“…To date, many studies continue to be published highlighting the potential of ALT and IAL as novel agents against various ailments, although their pharmacologic activities are unfortunately curtailed due to their low water solubility and low oral bioavailability [ 212 ]. However, ALT has been shown to have a rapid onset, without causing significant damage to normal animal tissues and organs in vivo [ 213 ].…”