title: Enhancement of intestinal permeability utilizing solid lipid nanoparticles increases γ-tocotrienol oral bioavailability.
abstract: γ-Tocotrienol (γ-T3), a member of the vitamin E family, has been reported to possess an anticancer activity. γ-T3 is a lipophilic compound with low oral bioavailability. Previous studies showed that γ-T3 has low intestinal permeability. Thus, we have hypothesized that enhancing γ-T3 intestinal permeability will increase its oral bioavailability. Solid lipid nanoparticles (SLN) were tested as a model formulation to enhance γ-T3 permeability and bioavailability. γ-T3 intestinal permeability was compared using in situ rat intestinal perfusion, followed by in vivo relative oral bioavailability studies. In addition, in vitro cellular uptake of γ-T3 from SLN was compared to mixed micelles (MM) in a time and concentration-dependent studies. To elucidate the uptake mechanism(s) of γ-T3 from SLN and MM the contribution of NPC1L1 carrier-mediated uptake, endocytosis and passive permeability were investigated. In situ studies demonstrated SLN has tenfold higher permeability than MM. Subsequent in vivo studies showed γ-T3 relative oral bioavailability from SLN is threefold higher. Consistent with in situ results, in vitro concentration dependent studies revealed γ-T3 uptake from SLN was twofold higher than MM. In vitro mechanistic characterization showed that while endocytosis contributes to γ-T3 uptake from both formulations, the reduced contribution of NPC1L1 to the transport of γ-T3, and passive diffusion enhancement of γ-T3 are primary explanations for its enhanced uptake from SLN. In conclusion, SLN successfully enhanced γ-T3 oral bioavailability subsequent to enhanced passive permeability.
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA.
authors.forename: Bilal S
authors.initials: BS
authors.lastname: Abuasal
authors.forename: Courtney
authors.initials: C
authors.lastname: Lucas
authors.forename: Breanne
authors.initials: B
authors.lastname: Peyton
authors.forename: Alaadin
authors.initials: A
authors.lastname: Alayoubi
authors.forename: Sami
authors.initials: S
authors.lastname: Nazzal
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sylvester
authors.forename: Amal
authors.initials: A
authors.lastname: Kaddoumi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002839:Chromans / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D002839:Chromans; D008055:Lipids; D014810:Vitamin E; C013649:plastochromanol 8