Abstract
Oleacein (OLEA) is one of the most important phenolic compounds in extra virgin olive oil in terms of concentration and health-promoting properties, yet there are insufficient data on its absorption and metabolism. Several non-human models have been developed to assess the intestinal permeability of drugs, among them, single-pass intestinal perfusion (SPIP), which is commonly used to investigate the trans-membrane transport of drugs in situ. In this study, the SPIP model and simultaneous luminal blood sampling were used to study the absorption and metabolism of OLEA in rats. Samples of intestinal fluid and mesenteric blood were taken at different times and the ileum segment was excised at the end of the experiment for analysis by LC–ESI–LTQ–Orbitrap–MS. OLEA was mostly metabolized by phase I reactions, undergoing hydrolysis and oxidation, and metabolite levels were much higher in the plasma than in the lumen. The large number of metabolites identified and their relatively high abundance indicates an important intestinal first-pass effect during absorption. According to the results, OLEA is well absorbed in the intestine, with an intestinal permeability similar to that of the highly permeable model compound naproxen. No significant differences were found in the percentage of absorbed OLEA and naproxen (48.98 ± 12.27% and 43.96 ± 7.58%, respectively).
Highlights
IntroductionThe small intestine is the main site for drug absorption after oral administration [1,2], and the intestinal epithelial membrane is the principle physiological barrier that chemicals must cross to enter the bloodstream and become bioavailable [3]
The stability of OLEA and the reference standard naproxen was evaluated prior to carrying out the intestinal permeability study, and both remained stable in the perfusion solution at 37 ◦ C (p > 0.05) for the length of the experiments, i.e., over 60 min (Figure S1)
The FTMS scan and MSn experiments allowed for the identification of OLEA (M1), four phase I metabolites (M2, M3, M4, and M5), and six phase II metabolites (M6, M7, M8, M9, M10, and M11)
Summary
The small intestine is the main site for drug absorption after oral administration [1,2], and the intestinal epithelial membrane is the principle physiological barrier that chemicals must cross to enter the bloodstream and become bioavailable [3]. In vitro, in situ, and in vivo models have been developed to investigate the transport mechanisms, intestinal permeability, and plasma pharmacokinetic profile of chemicals [4]. The in vivo models are the most clinically relevant because they include all the physiological factors that can affect absorption and bioavailability [1,4], but they are less useful for mechanistic studies. The in situ models, such as single-pass intestinal perfusion (SPIP), are commonly
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