Online citations, reference lists, and bibliographies.
← Back to Search

Enhancement Of Naringenin Bioavailability By Complexation With Hydroxypropoyl-β-Cyclodextrin

Maria Shulman, M. Cohen, A. Soto-Gutiérrez, H. Yagi, H. Wang, J. Goldwasser, Carolyn W. T. Lee‐Parsons, Ofra Benny-Ratsaby, M. Yarmush, Y. Nahmias
Published 2011 · Chemistry, Medicine

Cite This
Download PDF
Analyze on Scholarcy
Share
The abundant flavonoid aglycone, naringenin, which is responsible for the bitter taste in grapefruits, has been shown to possess hypolipidemic and anti-inflammatory effects both in vitro and in vivo. Recently, our group demonstrated that naringenin inhibits hepatitis C virus (HCV) production, while others demonstrated its potential in the treatment of hyperlipidemia and diabetes. However, naringenin suffers from low oral bioavailability critically limiting its clinical potential. In this study, we demonstrate that the solubility of naringenin is enhanced by complexation with β-cyclodextrin, an FDA approved excipient. Hydroxypropoyl-β-cyclodextrin (HPβCD), specifically, increased the solubility of naringenin by over 400-fold, and its transport across a Caco-2 model of the gut epithelium by 11-fold. Complexation of naringenin with HPβCD increased its plasma concentrations when fed to rats, with AUC values increasing by 7.4-fold and Cmax increasing 14.6-fold. Moreover, when the complex was administered just prior to a meal it decreased VLDL levels by 42% and increased the rate of glucose clearance by 64% compared to naringenin alone. These effects correlated with increased expression of the PPAR co-activator, PGC1α in both liver and skeletal muscle. Histology and blood chemistry analysis indicated this route of administration was not associated with damage to the intestine, kidney, or liver. These results suggest that the complexation of naringenin with HPβCD is a viable option for the oral delivery of naringenin as a therapeutic entity with applications in the treatment of dyslipidemia, diabetes, and HCV infection.
This paper references
10.1371/journal.pone.0012399
Transcriptional Regulation of Human and Rat Hepatic Lipid Metabolism by the Grapefruit Flavonoid Naringenin: Role of PPARα, PPARγ and LXRα
J. Goldwasser (2010)
Pharmaceutical applications of cyclodextrins
Rajewski (1996)
10.1016/J.JCONREL.2007.07.018
The utility of cyclodextrins for enhancing oral bioavailability.
R. Carrier (2007)
10.1016/J.NUT.2005.11.006
Activity and mRNA levels of enzymes involved in hepatic fatty acid oxidation in mice fed citrus flavonoids.
Doan Thi Thanh Huong (2006)
10.1208/pt060243
Cyclodextrins in drug delivery: An updated review
R. Challa (2008)
10.1038/sj.ejcn.1602543
Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects
F. I. Kanaze (2007)
10.1093/JN/131.2.235
Plasma kinetics and urinary excretion of the flavanones naringenin and hesperetin in humans after ingestion of orange juice and grapefruit juice.
I. Erlund (2001)
Toxicol Pathol
Vj Stella (2008)
10.1016/S0261-5614(03)00059-1
Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects.
U. J. Jung (2003)
10.1002/BDD.588
Pharmacokinetics of selected chiral flavonoids: hesperetin, naringenin and eriodictyol in rats and their content in fruit juices
J. Yáñez (2008)
10.1016/S0731-7085(03)00647-2
Improvement in solubility and dissolution rate of flavonoids by complexation with beta-cyclodextrin.
S. Tommasini (2004)
10.2337/DIABETES.54.6.1676
Inhibition of microsomal triglyceride transfer protein expression and apolipoprotein B100 secretion by the citrus flavonoid naringenin and by insulin involves activation of the mitogen-activated protein kinase pathway in hepatocytes.
E. Allister (2005)
Naringenin prevents dyslipidemia, apoB overproduction and hyperinsulinemia in LDL-receptor null mice with diet-induced insulin resistance. Running title: Naringenin prevents dyslipidemia
Erin E. Mulvihill (2009)
10.1002/0471141755
Current protocols in pharmacology
S. Enna (1998)
10.1039/b802662a
Dietary phenolics: chemistry, bioavailability and effects on health.
A. Crozier (2009)
10.1194/JLR.M800297-JLR200
Inhibition of apoB secretion from HepG2 cells by insulin is amplified by naringenin, independent of the insulin receptor
Emma M. Allister (2008)
10.1007/s10565-005-0085-6
The Caco-2 cell line as a model of the intestinal barrier: influence of cell and culture-related factors on Caco-2 cell functional characteristics
Y. Sambuy (2005)
10.1042/BJ3350433
Effects of cholesterol depletion by cyclodextrin on the sphingolipid microdomains of the plasma membrane.
S. Ilangumaran (1998)
10.1073/pnas.0906820106
Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance
Srivatsan Kidambi (2009)
Enna SJ, Williams M, eds
J Gao (2000)
10.1006/BBRC.1999.1695
Interactions of the flavonoid naringenin in the gastrointestinal tract and the influence of glycosylation.
R. Choudhury (1999)
10.2337/DIABETES.52.10.2554
Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation.
N. Borradaile (2003)
Insulin-like effects of naringenin on inhibition of apolipoprotein B secretion from HepG2 cells
EM Allister (2008)
Cyclodextrins
VJ Stella (2008)
10.1016/S0271-5317(99)00144-X
Hypocholesterolemic effects of dietary citrus juices in rabbits
E. Kurowska (2000)
10.1002/0471141755.ph0702s08
Estimating intestinal mucosal permeation of compounds using Caco-2 cell monolayers.
Jinnian Gao (2001)
10.1111/J.1527-3466.1999.TB00011.X
Antiatherogenic Properties of Naringenin, a Citrus Flavonoid
Lisa J. Wilcox (1999)
10.1016/0009-9236(95)90048-9
The fate of naringin in humans: A key to grapefruit juice‐drug interactions?
U. Fuhr (1995)
Transcriptional Regulation of Human and Rat Hepatic Lipid Metabolism by the Grapefruit Flavonoid Naringenin: Role of PPARa, PPARc and LXRa
J Goldwasser (2010)
10.1016/j.tox.2008.11.012
Naringenin protects against cadmium-induced oxidative renal dysfunction in rats.
J. Renugadevi (2009)
10.1023/A:1012136608249
Cyclodextrins: Their Future in Drug Formulation and Delivery
V. Stella (2004)
10.1081/PDT-100100556
Improvement of Solubility and Oral Bioavailability of Rutin by Complexation with 2-Hydroxypropyl-β-cyclodextrin
K. Miyake (2000)
10.1002/ptr.2504
Naringenin and hesperetin, two flavonoids derived from Citrus aurantium up‐regulate transcription of adiponectin
L. Liu (2008)
Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP.
Lisa J. Wilcox (2001)
10.1002/hep.22197
Apolipoprotein B–dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin
Y. Nahmias (2008)
10.2337/db09-0634
Naringenin Prevents Dyslipidemia, Apolipoprotein B Overproduction, and Hyperinsulinemia in LDL Receptor–Null Mice With Diet-Induced Insulin Resistance
Erin E. Mulvihill (2009)
10.1016/J.TRSL.2006.08.001
Hypocholesterolemic and antioxidative effects of naringenin and its two metabolites in high-cholesterol fed rats.
S. Jeon (2007)
10.1021/JS960075U
Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery.
R. Rajewski (1996)



This paper is referenced by
10.1007/s10787-018-00561-6
The citrus flavanone naringenin attenuates zymosan-induced mouse joint inflammation: induction of Nrf2 expression in recruited CD45+ hematopoietic cells
A. J. Bussmann (2019)
Studium tvorby inkluzních komplexů vybraných flavonoidů s cyklodextriny
Adriana Ščurková (2017)
10.1007/s12263-014-0425-3
Naringenin modulates skeletal muscle differentiation via estrogen receptor α and β signal pathway regulation
Marco Pellegrini (2014)
10.1007/s10311-020-01082-x
Methods to improve the solubility of therapeutical natural products: a review
Harsha Jain (2020)
10.3390/cryst10010010
Inclusion Complexes of Naringenin in Dimethylated and Permethylated β -Cyclodextrins: Crystal Structures and Molecular Dynamics Studies
Andreas Papaioannou (2019)
10.1016/j.phrs.2015.11.011
PPARα in lysosomal biogenesis: A perspective.
Arunava Ghosh (2016)
10.1016/B978-0-12-804307-3.00004-1
Cyclodextrins as encapsulation material for flavors and aroma
M. Kfoury (2016)
10.1021/ci5002668
ColBioS-FlavRC: A Collection of Bioselective Flavonoids and Related Compounds Filtered from High-Throughput Screening Outcomes
Sorin I. Avram (2014)
10.1208/s12249-017-0790-5
Formulation and Evaluation of Naringenin Nanosuspensions for Bioavailability Enhancement
Sonia Gera (2017)
10.1016/j.neuroscience.2013.09.029
Sesamol and naringenin reverse the effect of rotenone-induced PD rat model
M. S. Angeline (2013)
Cannabinoids delivery systems based on supramolecular inclusion complexes and polymeric nanocapsules for treatment of neuropathic pain
F. Astruc-Diaz (2012)
10.1111/J.1541-4337.2012.00201.X
History, Global Distribution, and Nutritional Importance of Citrus Fruits
Y. Liu (2012)
10.1016/J.MOLSTRUC.2016.10.059
Preparation, characterization, and in vitro anti-inflammatory evaluation of novel water soluble kamebakaurin/hydroxypropyl-β-cyclodextrin inclusion complex
A. Raza (2017)
10.13130/fuenmayor-bobadilla-carlos-alberto_phd2014-09-29
NANOFIBERS: TAILOR-MADE APPLICATIONS FOR THE FOOD AND BEVERAGE INDUSTRY
C. Bobadilla (2014)
10.1016/j.cbi.2015.11.014
Cytoprotection of pancreatic β-cells and hypoglycemic effect of 2-hydroxypropyl-β-cyclodextrin: sertraline complex in alloxan-induced diabetic rats.
V. Buko (2016)
10.1016/j.ejphar.2011.09.163
Naringenin suppresses the production of thymic stromal lymphopoietin through the blockade of RIP2 and caspase-1 signal cascade in mast cells.
P. Moon (2011)
10.1007/s11101-019-09650-y
Inclusion complex with cyclodextrins enhances the bioavailability of flavonoid compounds: a systematic review
Bruno dos Santos Lima (2019)
10.1111/jphp.12079
Mid‐infrared spectroscopy as a polymer selection tool for formulating amorphous solid dispersions
Lindsay A. Wegiel (2014)
10.1039/c3fo60063g
Flavonoids as dietary regulators of nuclear receptor activity.
Yishai Avior (2013)
10.1002/9781119227625.CH8
Encapsulation technologies for resveratrol in functional food
M. Chávarri (2017)
10.1016/B978-0-323-52727-9.00018-2
The Supramolecular Complex of Sertraline With Cyclodextrins: Physicochemical and Pharmacological Properties
V. Buko (2017)
10.1016/BS.AFNR.2019.02.014
Bioavailability of nanotechnology-based bioactives and nutraceuticals.
D. Jones (2019)
10.1371/journal.pone.0185652
Gold nanoparticles stabilized with βcyclodextrin-2-amino-4-(4-chlorophenyl)thiazole complex: A novel system for drug transport
I. Asela (2017)
10.1016/J.ARABJC.2017.12.004
Directly grown of 3D-Nickel oxide nano flowers on TiO 2 nanowire arrays by hydrothermal route for electrochemical determination of naringenin flavonoid in vegetable samples
M. S. Prasad (2017)
10.1016/j.ijpharm.2015.01.034
Preparation and evaluation of submicron-carriers for naringenin topical application.
Ming-Jun Tsai (2015)
10.1016/j.carbpol.2013.08.078
Cyclodextrins as encapsulation agents for plant bioactive compounds.
E. Pinho (2014)
10.1016/j.biopha.2017.01.157
Complexation of phytochemicals with cyclodextrin derivatives - An insight.
Vasanti Suvarna (2017)
10.1007/978-3-030-41838-0
Sustainable Agriculture Reviews 43: Pharmaceutical Technology for Natural Products Delivery Vol. 1 Fundamentals and Applications
A. Saneja (2020)
10.1080/03639045.2020.1747485
Sonication tailored enhance cytotoxicity of naringenin nanoparticle in pancreatic cancer: design, optimization, and in vitro studies
Md. Habban Akhter (2020)
10.1016/j.biopha.2019.109439
Adipose tissue as a possible therapeutic target for polyphenols: A case for Cyclopia extracts as anti-obesity nutraceuticals.
B. Jack (2019)
10.1007/978-1-62703-203-2_6
Carotenoid Bioavailability: Influence of Dietary Lipid and Fiber
S. Goltz (2013)
10.1002/APP.46885
Synthesis and antimicrobial applications of the inclusion complexes of β‐cyclodextrin copolymers with potassium sorbate
Yu Cao (2018)
See more
Semantic Scholar Logo Some data provided by SemanticScholar