Punicic acid ethyl ester, a superior absorption-enhancer over pomegranate seed oil, dramatically improves quercetin bioavailability via strong interaction and rapid lipolysis

Low oral bioavailability remains a major challenge for drug delivery. Fatty acids (FAs) and vegetable oils have attracted great interest as absorption enhancers due to their excellent compatibility. However, the difference in absorption-enhancing efficiency of various FA chemical forms and the underlying mechanisms remain unclear. In vegetable oils, FAs are confined within rigid triglyceride structures, whereas free FAs or their monoesters possess flexible carbon chains. We hypothesize that such molecular flexibility facilitates stronger drug interactions, resulting in greater absorption-enhancing capacity for FAs or their monoesters compared with parent oils. To validate this, punicic acid (PA) was isolated from pomegranate seed oil (PSO) and converted into its ethyl ester (PAEE). Employing quercetin (QU) as the model drug and oleic acid (OA) as a control, we systematically evaluated the effect of PAEE, PSO, OA, and their nanoemulsions (NE) on QU physiochemical characteristics. In vitro, the antibacterial activity followed the order of QU-PAEE > QU-PSO > QU-OA > QU. Among the oils, PAEE showed strongest protection on QU in gastrointestinal fluid, the greatest interaction with QU, and significantly faster lipolysis than PSO. NE formulations further amplified these effects. In vivo, PAEE, PSO, and OA increased QU oral bioavailability by 4.57-, 3.49-, and 3.07- fold, respectively, whereas their NE achieved 20.66-, 6.42-, and 6.19- fold increases. This study identifies PAEE as a highly efficient and safe absorption-enhancer and, more importantly, demonstrates that FA monoesters present markedly stronger absorption-enhancing efficiency than their parent oils, providing new insights for the design of lipid-based drug carriers.

• Publication year

  2026

• Venue

  International journal of pharmaceutics: X

• Publication date

  2026-01-01

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.ijpx.2026.100499PMID 41675219PMCID 12887365
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

• Synthesis of Antibacterial C 16 Cis ‐Unsaturated Fatty Acids by Transfer Semihydrogenation of Long‐Chain Alkynes Catalyzed by Palladium–Imidazo[1,5‐ a ]pyridine Carbene Complexes

  2025cited by this paper
• Permeability-Enhancing and Protective Effect on Small Intestine of Punicic Acid in Different Forms and Their Nanoemulsions With Low Toxicity

  2025cited by this paper
• Simple preparation and greatly improved oral bioavailability: The supersaturated drug delivery system of quercetin based on PVP K30

  2024cited by this paper
• Efficient extraction methods and callus culture of quercetin from Indian white radish: yield analysis via HPLC quantification and assessment of cytotoxic activity

  2024cited by this paper
• Targeting the Gut: A Systematic Review of Specific Drug Nanocarriers

  2024cited by this paper
• Nano Drug Delivery Strategies for an Oral Bioenhanced Quercetin Formulation

  2023cited by this paper
• Zein-based nanospheres and nanocapsules for the encapsulation and oral delivery of quercetin.

  2023cited by this paper
• Natural Ingredients of Transdermal Drug Delivery Systems as Permeation Enhancers of Active Substances through the Stratum Corneum

  2023cited by this paper
• Vegetable oils composition affects the intestinal lymphatic transport and systemic bioavailability of co-administered lipophilic drug cannabidiol.

  2022cited by this paper
• Structure-activity relationship of dietary flavonoids on pancreatic lipase

  2022cited by this paper
• Enhanced Bioavailability and Pharmacokinetics of a Natural Self-Emulsifying Reversible Hybrid-Hydrogel System of Quercetin: A Randomized Double-Blinded Comparative Crossover Study

  2022cited by this paper
• Dietary fatty acid-mediated protein encapsulation simultaneously improving the water-solubility, storage stability, and oral absorption of astaxanthin

  2022cited by this paper
• Isolation of punicic acid from pomegranate seed oil by modified freeze crystallization and response surface methodology

  2022cited by this paper
• In Vitro Gastrointestinal Stability of Lipophilic Polyphenols is Dependent on their Oil-Water Partitioning in Emulsions: Studies on Curcumin, Resveratrol, and Quercetin.

  2021influential reference
• Intestinal metabolism and absorption mechanism of multi-components in Gaultheria leucocarpa var. yunnanensis - An assessment using in situ and in vitro models, comparing gut segments in pathological with physiological conditions.

  2021cited by this paper
• Enhancement of oral bioavailability of quercetin by metabolic inhibitory nanosuspensions compared to conventional nanosuspensions

  2021influential reference
• Physicochemical characterization of oil, antioxidant potential, and phenolic profile of seeds isolated from Tunisian pomegranate (Punica granatum L.) cultivars.

  2021cited by this paper
• Preparation of quercetin–nicotinamide cocrystals and their evaluation under in vivo and in vitro conditions

  2020cited by this paper
• Nanoemulsion preconcentrate of a pentacyclic triterpene for improved oral efficacy: Formulation design and in-vivo antimalarial activity

  2020cited by this paper
• Quercetin: Its Main Pharmacological Activity and Potential Application in Clinical Medicine

  2020cited by this paper
• A Non-Lipolysis Nanoemulsion Improved Oral Bioavailability by Reducing the First-Pass Metabolism of Raloxifene, and Related Absorption Mechanisms Being Studied

  2020influential reference
• Impact of dietary intake of medium-chain triacylglycerides on the intestinal absorption of poorly permeable compounds.

  2019cited by this paper
• Improving Correlations Between Drug Solubilization and In Vitro Lipolysis by Monitoring the Phase Partitioning of Lipolytic Species for Lipid-Based Formulations.

  2019cited by this paper
• UPLC-MS/MS quantification of quercetin in plasma and urine following parenteral administration

  2019influential reference
• Intestinal Permeability and Drug Absorption: Predictive Experimental, Computational and In Vivo Approaches

  2019cited by this paper
• Casein nanoparticles in combination with 2-hydroxypropyl-β-cyclodextrin improves the oral bioavailability of quercetin.

  2019cited by this paper
• Bacteriostatic Effect of Quercetin as an Antibiotic Alternative In Vivo and Its Antibacterial Mechanism In Vitro.

  2018cited by this paper
• Pomegranate Seed Oil Enhances the Percutaneous Absorption of trans-Resveratrol.

  2018influential reference
• Formulation of Pomegranate Seed Oil: A Promising Approach of Improving Stability and Health-Promoting Properties

  2018cited by this paper
• Two new unsaturated fatty acids from the whole plant of Pothos chinensis

  2017cited by this paper
• Enhanced Oral Bioavailability of Domperidone with Piperine in Male Wistar Rats: Involvement of CYP3A1 and P-gp Inhibition.

  2017influential reference
• Pomegranate as a promising opportunity in medicine and nanotechnology

  2017cited by this paper
• Zein nanoparticles for oral delivery of quercetin: Pharmacokinetic studies and preventive anti-inflammatory effects in a mouse model of endotoxemia.

  2017cited by this paper
• Antimicrobial Activity of Selected Polyphenols and Capsaicinoids Identified in Pepper (Capsicum annuum L.) and Their Possible Mode of Interaction

  2017cited by this paper
• Controlling the gastrointestinal fate of nutraceutical and pharmaceutical-enriched lipid nanoparticles: From mixed micelles to chylomicrons

  2017cited by this paper
• Modeling the dose effects of soybean oil in salad dressing on carotenoid and fat-soluble vitamin bioavailability in salad vegetables.

  2017cited by this paper
• Oleic acid complex of bovine α-lactalbumin induces eryptosis in human and other erythrocytes by a Ca(2+)-independent mechanism.

  2015cited by this paper
• Punica granatum and its therapeutic implications on breast carcinogenesis: A review

  2015cited by this paper
• Pomegranate Seed Oil Exerts Synergistic Effects with trans-Resveratrol in a Self-nanoemulsifying Drug Delivery System.

  2015cited by this paper
• Lipase-catalyzed synthesis of acid-degradable poly(β-thioether ester) and poly(β-thioether ester-co-lactone) copolymers

  2015influential reference
• In vivo methods for drug absorption - comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects.

  2014cited by this paper
• Effect of human and simulated gastric juices on the digestion of whey proteins and carboxymethylcellulose-stabilised O/W emulsions.

  2014cited by this paper
• Quercetin-containing self-nanoemulsifying drug delivery system for improving oral bioavailability.

  2014cited by this paper
• BIOAVAILABILITY ENHANCDEMENT OF POORLY SOLUBLE DRUGS BY SMEDDS: A REVIEW

  2013cited by this paper
• The antibacterial activity of various saturated and unsaturated fatty acids against several oral pathogens.

  2013cited by this paper
• Fatty acids as therapeutic auxiliaries for oral and parenteral formulations.

  2013cited by this paper
• Influence of Vegetable Oils on Micellization of Lutein in a Simulated Digestion Model

  2011cited by this paper
• Intestinal lymphatic transport for drug delivery

  2011cited by this paper
• Molecular docking: a powerful approach for structure-based drug discovery.

  2011cited by this paper
• Antioxidant properties of major metabolites of quercetin

  2011cited by this paper
• Oral bioavailability of quercetin from different quercetin glycosides in dogs.

  2010influential reference
• Characterisation of anti-Staphylococcus aureus activity of quercetin

  2010cited by this paper
• Glucuronidated and sulfated metabolites of the flavonoid quercetin prevent endothelial dysfunction but lack direct vasorelaxant effects in rat aorta.

  2009cited by this paper
• Pomegranate oil analysis with emphasis on MALDI-TOF/MS triacylglycerol fingerprinting.

  2007cited by this paper
• Prediction of human absorption of natural compounds by the non-everted rat intestinal sac model.

  2006cited by this paper

• No citing papers are available for this paper.