Enhancement of naringenin bioavailability by complexation with hydroxypropoyl-β-cyclodextrin

Maria Shulman, Merav Cohen, Alejandro Soto-Gutierrez, Hiroshi Yagi, Hongyun Wang, Jonathan Goldwasser, Carolyn W. Lee-Parsons, Ofra Benny-Ratsaby, Martin L. Yarmush, Yaakov Nahmias

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere18033
JournalPLoS One
Volume6
Issue number4
DOIs
Publication statusPublished - 2011
Externally publishedYes

Fingerprint

naringenin
cyclodextrins
Cyclodextrins
Complexation
Biological Availability
bioavailability
Hepatitis C virus
hyperlipidemia
Medical problems
Viruses
Hepacivirus
Liver
Solubility
diabetes
solubility
mouth
Citrus paradisi
liver
Peroxisome Proliferator-Activated Receptors
blood chemistry

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Shulman, M., Cohen, M., Soto-Gutierrez, A., Yagi, H., Wang, H., Goldwasser, J., ... Nahmias, Y. (2011). Enhancement of naringenin bioavailability by complexation with hydroxypropoyl-β-cyclodextrin. PLoS One, 6(4), [e18033]. https://doi.org/10.1371/journal.pone.0018033

Enhancement of naringenin bioavailability by complexation with hydroxypropoyl-β-cyclodextrin. / Shulman, Maria; Cohen, Merav; Soto-Gutierrez, Alejandro; Yagi, Hiroshi; Wang, Hongyun; Goldwasser, Jonathan; Lee-Parsons, Carolyn W.; Benny-Ratsaby, Ofra; Yarmush, Martin L.; Nahmias, Yaakov.

In: PLoS One, Vol. 6, No. 4, e18033, 2011.

Research output: Contribution to journalArticle

Shulman, M, Cohen, M, Soto-Gutierrez, A, Yagi, H, Wang, H, Goldwasser, J, Lee-Parsons, CW, Benny-Ratsaby, O, Yarmush, ML & Nahmias, Y 2011, 'Enhancement of naringenin bioavailability by complexation with hydroxypropoyl-β-cyclodextrin', PLoS One, vol. 6, no. 4, e18033. https://doi.org/10.1371/journal.pone.0018033
Shulman, Maria ; Cohen, Merav ; Soto-Gutierrez, Alejandro ; Yagi, Hiroshi ; Wang, Hongyun ; Goldwasser, Jonathan ; Lee-Parsons, Carolyn W. ; Benny-Ratsaby, Ofra ; Yarmush, Martin L. ; Nahmias, Yaakov. / Enhancement of naringenin bioavailability by complexation with hydroxypropoyl-β-cyclodextrin. In: PLoS One. 2011 ; Vol. 6, No. 4.
@article{64c600f3b1bf44a99aa408908ececc08,
title = "Enhancement of naringenin bioavailability by complexation with hydroxypropoyl-β-cyclodextrin",
abstract = "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.",
author = "Maria Shulman and Merav Cohen and Alejandro Soto-Gutierrez and Hiroshi Yagi and Hongyun Wang and Jonathan Goldwasser and Lee-Parsons, {Carolyn W.} and Ofra Benny-Ratsaby and Yarmush, {Martin L.} and Yaakov Nahmias",
year = "2011",
doi = "10.1371/journal.pone.0018033",
language = "English",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - Enhancement of naringenin bioavailability by complexation with hydroxypropoyl-β-cyclodextrin

AU - Shulman, Maria

AU - Cohen, Merav

AU - Soto-Gutierrez, Alejandro

AU - Yagi, Hiroshi

AU - Wang, Hongyun

AU - Goldwasser, Jonathan

AU - Lee-Parsons, Carolyn W.

AU - Benny-Ratsaby, Ofra

AU - Yarmush, Martin L.

AU - Nahmias, Yaakov

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79953748950&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953748950&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0018033

DO - 10.1371/journal.pone.0018033

M3 - Article

C2 - 21494673

AN - SCOPUS:79953748950

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

M1 - e18033

ER -