Original articleEffects of friedelin on the intestinal permeability and bioavailability of apigenin
Introduction
Apigenin (4′,5,7-trihydroxyflavone, Fig. 1) is a member of the flavone subclass of flavonoids and present in many fruits and vegetables including parsley and celery [1]. Apigenin has been recognized as a traditional or alternative medicine with diverse biological functions, including antioxidant, antimutagenic [2], anticancer [3], neuroprotective [4], and anti-inflammatory [5] activities. Despite the health benefits afforded by apigenin, it has a relatively low bioavailability of approximately 3–5% [6], owing to poor permeation across gastrointestinal epithelia.
Bioavailability is defined as the degree and rate at which a substance is absorbed into a living system, thereby accessing the site of action. In most cases, when a medicine is administered orally, its bioavailability is decreased owing to incomplete absorption and first-pass metabolism. Certain bioactive compounds enhance the bioavailability of active substances [7]. Piperine was validated as the world’s first bioavailability enhancer (bioenhancer) in the 1979 [8]. The possible mechanisms for the bioavailability enhancing activity of piperine include increased blood supply to the gastrointestinal tract, decreased gastrointestinal emptying, and inhibition of metabolizing enzymes and P-glycoprotein (P-gp) [9], [10], [11]. The control of intestinal P-gp transporters has been considered as a key step in enhancing the bioavailability of active substances [12].
Friedelin, a triterpenoid, shows various functional properties such as anti-inflammatory, anti-oxidant [13] and gastroprotective effects [14]. Since there were no previous reports on the ability of friedelin to modulate the absorption or bioavailability of active compounds, this study investigated the possible application of friedelin to enhance the bioavailability of apigenin, using a human Caco-2 cell monolayer, single-pass intestinal perfusion, and by pharmacokinetic analysis.
Section snippets
Caco-2 cell culture
Caco-2 cells (3 × 105 cells/membrane) were seeded in 24-well Transwell inserts (Corning Life Sciences, Lowell, MA, USA) in Dulbecco’s modified Eagle’s medium (DMEM; Hyclone, Logan, UT, USA) containing high glucose and supplemented with 10% fetal bovine serum (FBS; Hyclone, Logan, UT, USA), 1% non-essential amino acids (Gibco, Grand Island, NY, USA), 100 units/mL penicillin and 100 μg/mL streptomycin (Gibco, Grand Island, NY, USA). Cells were maintained for 20 days at 37 °C in a humidified atmosphere
Permeability study in vitro and in situ
The difference in absorption rate of apigenin in Caco-2 cells was investigated in the absence or presence of friedelin. The Papp of apigenin in the presence of friedelin increased from (9.29 ± 0.13) x 10−6 cm/s to (15.13 ± 1.29) x 10−6 cm/s indicating that the presence of friedelin significantly enhanced the absorption of apigenin across the Caco-2 cell monolayer (Table 1).
The enhanced intestinal permeability observed in vitro experiments cell lines was further validated by the use of a single-pass
Discussion
Despite the biological and health benefits of flavonoids, their poor absorption, rapid metabolism, and inactivity of metabolic products on target tissues severely curtails their further utilization [19]. Therefore, it is important to increase the bioavailability of flavonoids by increasing gut permeability and/or controlling metabolism. Researchers have searched for bioenhancers that could enhance the bioavailability of active compounds by controlling gut permeation and/or metabolic enzymes [20]
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These authors contributed equally to this work.