title: Enhancement of naringenin bioavailability by complexation with hydroxypropyl-β-cyclodextrin. [corrected].
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 C(max) 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.
authors.affiliation: Center for Bioengineering, School of Computer Science & Engineering, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Maria
authors.initials: M
authors.lastname: Shulman
authors.forename: Merav
authors.initials: M
authors.lastname: Cohen
authors.forename: Alejandro
authors.initials: A
authors.lastname: Soto-Gutierrez
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yagi
authors.forename: Hongyun
authors.initials: H
authors.lastname: Wang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Goldwasser
authors.forename: Carolyn W
authors.initials: CW
authors.lastname: Lee-Parsons
authors.forename: Ofra
authors.initials: O
authors.lastname: Benny-Ratsaby
authors.forename: Martin L
authors.initials: ML
authors.lastname: Yarmush
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Nahmias
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D018938:Caco-2 Cells; D004032:Diet; D044950:Flavanones / Q000493:pharmacokinetics*; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility / Q000187:drug effects; D012996:Solutions; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D044950:Flavanones; D008079:Lipoproteins, VLDL; D012996:Solutions; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C005273:naringenin; D005947:Glucose