Nonlinear Absorption Kinetics of Self-Emulsifying Drug Delivery Systems (SEDDS) Containing Tocotrienols as Lipophilic Molecules: In Vivo and In Vitro Studies

Abstract

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.

Vitamin E Transporters in Cancer Therapy

“…However, reported poor oral bioavailability of vitamin E isoforms limits their utilization as therapeutic agents in cancer therapy. The limited bioavailability of vitamin E and isoforms could be attributed to the following reasons: (1) vitamin E members are lipophilic in nature that are practically insoluble in water and display high solubility in organic solvents (about 10 μg/ml) (64,65), and (2) available studies, including ours, have reported vitamin E isoforms as substrates for intestinal transport proteins, which become saturated in the presence of high concentrations, thus limiting their oral bioavailability and prompting nonlinear absorption kinetics (66,67).…”

“…Our results confirmed that both isoforms are substrates of NPC1L1 and that α-tocopherol is transported at significantly higher rates, however with lower affinity, compared with γ-tocotrienol, which could be due to the higher passive permeability of α-tocopherol (64). In addition, in vitro and in vivo studies performed by us demonstrated that like the γ-isoform, δ-tocotrienol transport is mediated by NPC1L1 and that the intestinal absorption of both tocotrienols was capacity limited and saturable, thus limiting their bioavailability (66,67).…”

“…Using an in situ rat intestinal perfusion model, we showed that the intestinal uptake of γ-tocotrienol is concentration-dependent and a saturable process. Results from the in situ and additional in vitro inhibition studies revealed the significant contribution of NPC1L1 to the uptake and transport of γ-tocotrienol across the cell membrane (66,67). The in vitro interaction kinetics of γ-tocotrienol with NPC1L1 was further examined in NPC1L1-transfected cells and was compared with those of α-tocopherol.…”

“…Further studies investigated the incorporation γ-and δ-tocotrienol in self-emulsifying drug-delivery systems (SEDDS) on their bioavailability. Findings of these studies showed a significant increase in the solubility, permeability, and oral bioavailability of γ-and δ-tocotrienols both in vitro and in vivo (67,86). To explain the enhanced intestinal permeability and bioavailability of γ-and δ-tocotrienol delivered as either SLN or SEDDS compared with their delivery as mixed micelles, in vitro mechanistic studies were performed (67,85,86).…”

“…Findings of these studies showed a significant increase in the solubility, permeability, and oral bioavailability of γ-and δ-tocotrienols both in vitro and in vivo (67,86). To explain the enhanced intestinal permeability and bioavailability of γ-and δ-tocotrienol delivered as either SLN or SEDDS compared with their delivery as mixed micelles, in vitro mechanistic studies were performed (67,85,86). Results of these studies revealed that packaging γ-and δ-tocotrienol in SLN or SEDDS delivery systems were able to enhance both isoforms' intestinal permeability and bioavailability as a result of the enhanced passive permeability and reduced contribution of NPC1L1 to the transport of both isoforms (67,85,86).…”