Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats

Abstract

Oleocanthal (OLC), a phenolic compound of extra virgin olive oil (EVOO), has emerged as a potential therapeutic agent against a variety of diseases due to its anti-inflammatory activity. The aim of the present study is to explore its in vivo intestinal absorption and metabolism. An in situ perfusion technique in rats was used, involving simultaneous sampling from the luminal perfusate and mesenteric blood. Samples were analysed by UHPLC–MS–MS for the presence of oleocanthal (OLC) and its metabolites. OLC was mostly metabolized by phase I metabolism, undergoing hydration, hydrogenation and hydroxylation. Phase II reactions (glucuronidation of hydrogenated OLC and hydrated metabolites) were observed in plasma samples. OLC was poorly absorbed in the intestine, as indicated by the low effective permeability coefficient (2.23 ± 3.16 × 10−5 cm/s) and apparent permeability coefficient (4.12 ± 2.33 × 10−6 cm/s) obtained relative to the values of the highly permeable reference compound levofloxacin (LEV). The extent of OLC absorption reflected by the area under the mesenteric blood-time curve normalized by the inlet concentration (AUC) was also lower than that of LEV (0.25 ± 0.04 vs. 0.64 ± 0.03, respectively). These results, together with the observed intestinal metabolism, suggest that OLC has a moderate-to-low oral absorption; but higher levels of OLC are expected to reach human plasma vs. rat plasma.

Comment on López-Yerena et al. “Absorption and Intestinal Metabolic Profile of Oleocanthal in Rats” Pharmaceutics 2020, 12, 134

“…Besides, the idea of the in-situ perfusion studies is to omit the solubility and evaluate the permeability. While the results provided do not support (-)-oleocanthal as a BCS class II compound, the authors' discussion of (-)-oleocanthal BCS classification is confusing and not justified [1]. Did the authors conclude that (-)-oleocanthal is a BCS class II compound based on presented results, or based on its assumed physicochemical properties (low solubility and relatively high lipophilicity)?…”

“…The authors of López-Yerena et al (2020) [1] neither declared the purity of the used (-)-oleocanthal by any analytical technique nor did they attempt to confirm its identity by any chromatographic and/or spectroscopic tools. This is very important due to the high instability and sensitivity of S-(-)-oleocanthal to air, light, and moisture, and the close structural similarity of several related secoiridoids present in EVOO.…”

“…Hemiacetal and acetal formation could significantly minimize, if not nullifying the availability of (-)-oleocanthal, which will ultimately complicate the detection of (-)-oleocanthal and related metabolites. Additionally, the structure shown for metabolite B in the title paper [1] is an inaccurate interpretation for the correct gem-diol analog of (-)-oleocanthal, which is formed because of water addition to the C-3 aldehyde, as shown in Figure 2 and reports in the literature [2][3][4]. The only way to confirm the listed structure B is to run detailed spectroscopic analyses including 2D-NMR experiments, like HMBC or 2D-INADEQUATE and mass-mass fragmentation studies.…”

“…The authors did not explicitly indicate whether they used this fragment or any MS–MS fragmentation of any obtained peak to confirm the metabolites’ identity and correlate them with the tyrosol moiety of the parent (-)-oleocanthal via obtaining this diagnostic fragment, as shown in Figure 3 . There was no interpretation of the fragments listed in Table 1 [ 1 ], nor any proposed potential fragmentation schemes, which clearly indicate mass–mass fragmentation was not used for metabolites identity confirmation. Furthermore, the authors did not explain why the metabolism will target breaking the α,β-unsaturated conjugation Δ 8,9 system by hydration and hydrogenation and leave the highly reactive C-3 aldehyde unreacted [ 2 , 3 , 4 ].…”

Natural Bioactive Compounds Useful in Clinical Management of Metabolic Syndrome

“…This data proposes that oleocanthal plays a key role in the modulation of inflammatory processes at the level of adipose tissue and could therefore improve the chronic low-grade inflammatory state, typical of obesity-related diseases and MetS [ 266 ]. However, in vivo pharmacokinetic studies conducted in rats demonstrated a low intestinal absorption of oleocanthal [ 278 ]. Human studies investigating the oleocanthal bioavailability after EVOO assumption are limited.…”