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.