Investigating the Double-Peak Phenomenon in Oral Pharmacokinetics of Eurycoma longifolia quassinoids in Lipid-Based Solid Dispersion

α(21)-Epoxyeurycomanone (EP) and eurycomanone (EN), the polar quassinoids of Eurycoma longifolia extract (TAF2) formulated as a lipid-based solid dispersion (TAF2-SD) to increase sperm count for oligospermic infertility, displayed improvement of oral pharmacokinetics and bioavailability in rats over the non-formulated TAF2 extract. The plasma concentration-time curves of the quassinoids in both preparations displayed double-peak phenomenon, similarly observed in BCS Class 3 drugs that are highly hydrophilic and of low phospholipid membrane permeability, which therefore prompted investigation of the contributing factors. The results following the oral co-administration of TAF2-SD with the gastrointestinal transit markers indicated that less than 50% w/w of EP and EN were absorbed in the rat small intestine prior to 2.5 h, the gastric emptying time of 50% w/w theophylline marker absorption. More than 70% w/w of the quassinoids were absorbed in the colon after 8 h, the detection of 50% w/w sulfapyridine, the hydrolyzed metabolite of sulfasalazine marker. The non-formulated TAF2 extract at 0.028 ppm and its major quassinoid, EN at 0.005 ppm reduced acetylcholine-and histamine-induced contractions of the guinea pig ileum, suggesting that the muscle relaxant effect contributed to the delay in gastric-emptying and absorption in the intestine. In conclusion, the formulated quassinoids improved the oral bioavailability without changing the double-peak pharmacokinetic profile, and reduced gut motility causing delayed gastric emptying and intestinal absorption.