Physicochemical Effects of the Major Quassinoids in a Standardized Eurycoma longifolia Extract (Fr 2) on the Bioavailability and Pharmacokinetic Properties, and their Implications for Oral Antimalarial Activity

Abstract

A simple validated LC-UV method for the phytochemical analysis of four bioactive quassinoids, 13α(21)-epoxyeurycomanone (EP), eurycomanone (EN), 13α,21-dihydroeurycomanone (ED) and eurycomanol (EL) in rat plasma following oral (200 mg/kg) and intravenous administration (10 mg/kg) of a standardized extract Fr 2 of Eurycoma longifolia Jack was developed for pharmacokinetic and bioavailability studies. The extract Fr 2 contained 4.0%, 18.5%, 0.7% and 9.5% of EP, EN, ED and EL, respectively. Following intravenous administration, EP displayed a relatively longer biological half-life (t ½ = 0.75 ± 0.25 h) due primarily to its lower elimination rate constant (k e) of 0.84 ± 0.26 h-1) when compared with the t ½ of 0.35 ± 0.04 h and k e of 2.14 ± 0.27 h-1 , respectively of EN. Following oral administration, EP showed a higher C max of 1.61± 0.41 μg/mL over that of EN (C max = 0.53 ± 0.10 μg/mL). The absolute bioavailability of EP was 9.5-fold higher than that of EN, not because of chemical degradation since both quassinoids were stable at the simulated gastric pH of 1. Instead, the higher log K ow value of EP (-0.43) contributed to greater membrane permeability over that of EN (log K ow =-1.46) at pH 1. In contrast, EL, being in higher concentration in the extract than EP, was not detected in the plasma after oral administration because of substantial degradation by the gastric juices after 2 h. Similarly, ED, being unstable at the acidic pH and together with its low concentration in Fr 2, was not detectable in the rat plasma. In conclusion, upon oral administration of the bioactive standardized extract Fr 2, EP and EN may be the only quassinoids contributing to the overall antimalarial activity; this is worthy of further investigation.

Acute, Reproductive Toxicity and Two‐generation Teratology Studies of a Standardized Quassinoid‐rich Extract of Eurycoma longifolia Jack in Sprague–Dawley Rats

“…The findings of the fetal morphological, visceral and skeletal studies of the TAF273‐treated groups compared to those of the non‐treated control indicated a non‐teratogenic effect of TAF273 at 100 mg/kg dose level. Furthermore, the possible toxic accumulation of chemicals in the foetus (Eriksson et al ., ) may not arise since the bioavailability and absorption of the quassinoids from TAF273 were relatively low, due to their polarity, short half‐life and high elimination rate (Low et al ., ; Chan, )…”

“…The findings of the fetal morphological, visceral and skeletal studies of the TAF273-treated groups compared to those of the non-treated control indicated a non-teratogenic effect of TAF273 at 100 mg/kg dose level. Furthermore, the possible toxic accumulation of chemicals in the foetus (Eriksson et al, 1973) may not arise since the bioavailability and absorption of the quassinoids from TAF273 were relatively low, due to their polarity, short half-life and high elimination rate (Low et al, 2011;Chan, 2012) In conclusion, the no-observed adverse effect level (NOAEL) of TAF273 as observed from the reproductive toxicity and teratology studies in rats of both sexes was 100 mg/kg (equivalent to 32 mg/kg of total quassinoids). The dose was at least 10-and 20-fold lower than the acute lethal dose in female and male rats, respectively.…”

Antiadipogenic effects of a standardized quassinoids‐enriched fraction and eurycomanone from Eurycoma longifolia

“…The standardized quassinoids‐enriched fraction of EL from the root was prepared following the method established previously by Low, Das, and Chan (). SQEL contains 14.49 ± 0.26% of eurycomanone, 7.39 ± 0.17% epoxyeurycomanone, 0.72 ± 0.06% 13,21‐dihydroeurycomanone, and 9.54 ± 0.22% w /w eurycomanol (Al‐Salahi et al, ; Low, Teh, Yuen, & Chan, ). The pure compound, eurycomanone, was purchased, and its purity (>96%) was verified using HPLC (Chengdu Biopurify Phytochemicals Ltd., Chengdu, China).…”

LC-Based Metabolomics and Multivariate Analyses Reveal Metabolite Variations in Different Propagation Methods ofEurycoma longifoliaRoots Harvested at Different Ages and Locations

“…Eurycomanone is the most abundant phytochemical quassinoids in E. longifolia roots [24, 27 and 29] which has stable composition (not easily metabolized) [30]. A study by Low et al [31] reported that eurycomanone and 13α-(21)-epoxyeurycomanone possessed good physicochemical properties such as chemical stability, plasma stability, plasma protein binding, solubility and permeability. In fact, both of them are the main quassinoids contributing to the overall antimalarial activity of E. longifolia .…”