title: Nonlinear absorption kinetics of self-emulsifying drug delivery systems (SEDDS) containing tocotrienols as lipophilic molecules: in vivo and in vitro studies.
abstract: Self-emulsifying drug delivery systems (SEDDS) have been broadly used to promote the oral absorption of poorly water-soluble drugs. The purpose of the current study was to evaluate the in vivo oral bioavailability of vitamin E isoforms, δ-tocotrienol (δ-T3) and γ-tocotrienol (γ-T3) administered as SEDDS, as compared to commercially available UNIQUE E® Tocotrienols capsules. Results from studies in rats showed that low dose treatment with δ-T3 (90%) and γ-T3 (10%) formulated SEDDS showed bioavailability of 31.5% and 332%, respectively. However, bioavailability showed a progressive decrease with increased treatment dose that displayed nonlinear absorption kinetics. Additional in vitro studies examining cellular uptake studies in Caco 2 cells revealed that the SEDDS formulation increased passive permeability of δ-T3 and γ-T3 by threefold as compared to the commercial capsule formulation. These studies also showed that free surfactants decreased δ-T3 and γ-T3 absorption. Specifically, combined treatment cremophor EL or labrasol with tocotrienols caused a 60-85% reduction in the cellular uptake of δ-T3 and γ-T3 and these effects appear to result from surfactant-induced inhibition of the δ-T3 and γ-T3 transport protein Niemann-Pick C1-like 1 (NPC1L1). In summary, results showed that SEDDS formulation significantly increases the absorption and bioavailability δ-T3 and γ-T3. However, this effect is self-limiting because treatment with increasing doses of SEDDS appears to be associated with a corresponding increase in free surfactants levels that directly and negatively impact tocotrienol transport protein function and results in nonlinear absorption kinetics and a progressive decrease in δ-T3 and γ-T3 absorption and bioavailability.
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA.
authors.forename: Saeed
authors.initials: S
authors.lastname: Alqahtani
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: D000042:Absorption / Q000187:drug effects / Q000502:physiology; D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D045703:Emulsifying Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007700:Kinetics; D008055:Lipids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D017711:Nonlinear Dynamics; D051381:Rats; D017207:Rats, Sprague-Dawley; D024508:Tocotrienols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D045703:Emulsifying Agents; D008055:Lipids; D024508:Tocotrienols