Elsevier

Pharmacological Reports

Volume 69, Issue 5, October 2017, Pages 1044-1048
Pharmacological Reports

Original article
Effects of friedelin on the intestinal permeability and bioavailability of apigenin

https://doi.org/10.1016/j.pharep.2017.04.012Get rights and content

Abstract

Background

Although apigenin possesses diverse pharmacological activities, its utilization as a bioactive substance is limited by poor oral bioavailability. The aim of this study was to improve the bioavailability of apigenin by co-administration of friedelin.

Methods

To achieve this, the intestinal permeability of apigenin in the absence or presence of friedelin was investigated in both Caco-2 cells and single-pass rat intestinal perfusion models.

Results

The apparent permeability coefficients (Papp) of apigenin in the presence of friedelin were substantially increased by 1.63- and 1.60-fold in Caco-2 cells and single-pass rat intestinal perfusion models, respectively. Such increases in the Papp indicated that friedelin could significantly enhance the absorption of apigenin into the body. The increased bioavailability of apigenin in rats following the oral administration of apigenin 50 mg/kg body weight with friedelin 50 mg/kg body weight was further confirmed by increases in the peak concentration of apigenin (Cmax), elimination half-life (T1/2) and area under the plasma concentration-time curve (AUC).

Conclusions

Friedelin suppressed ATPase activity of P-glycoprotein (P-gp) indicated that the improved bioavailability of apigenin may be ascribed to P-gp inhibition by the co-administered friedelin.

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]

References (39)

Cited by (14)

  • The influence of friedelin, resinone, tingenone and betulin of compounds on chondrogenic differentiation of porcine adipose-derived mesenchymal stem cells (pADMSCs)

    2022, Biochimie
    Citation Excerpt :

    Friedelin is a triterpenoid that has shown excellent anti-inflammatory, free radical scavenging, analgesic, antioxidant activities and antipyretic properties in animal models [19,20]. Triterpenoids have attracted attention as hepatoprotective, wound healing, anti-inflammatory, anti-bacterial, antiviral and anti-tumour agents [19,21–23]. Tingenone compounds are natural triterpenoids known for their promising clinical potential for various forms of cancer chemoprevention and treatments [24–27].

  • Deuteration enhances the anti-tumor effects and relative anti-inflammatory effects via affecting proliferation and apoptosis

    2021, Heliyon
    Citation Excerpt :

    However, because of its low solubility and high permeability, it is categorised as a Biopharmaceutics Classification System Class II drug, meaning that requires a relatively longer effect period and higher uptake efficiency [1, 10, 11]. Deuteration, in which a hydrogen atom in a small molecule is replaced by deuterium, is an easy way to improve the bioavailability of biopharmaceuticals as well as to avoid extensive systemic waste in drug delivery, as the kinetic isotope effect results in a lower rate of metabolism of the deuterated drug molecule, allowing more time for it to take effect [12, 13]. As the first batch of US Food and Drug Administration-approved deuterated drugs, deuterated tetrabenazine (Austedo) has shown superior effects to its non-deuterated form in treating Huntington's chorea [14].

  • HPLC-DAD profiles and pharmacological insights of Onobrychis argyrea subsp isaurica extracts

    2018, Computational Biology and Chemistry
    Citation Excerpt :

    Besides, extensive preclinical and clinical studies revealed the neuroprotective potential of apigenin in Alzheimer's and Parkinson's diseases (Nabavi et al., 2018). With respect to the significant therapeutic benefits of apigenin several mechanisms to enhance bioavailability of the compound have been reported and are under study (Altamimi et al., 2018; Lee et al., 2017). The potential of O. argyrea extracts to inhibit enzymes associated to major health complications such as Alzheimer's disease, diabetes, and epidermal hyperpigmentation disorders, was assessed.

View all citing articles on Scopus
1

These authors contributed equally to this work.

View full text