Increased intestinal permeation and modulation of presystemic metabolism of resveratrol formulated into self-emulsifying drug delivery systems.

Despite various beneficial biological properties, resveratrol lacks therapeutic applications because of poor bioavailability due to variable absorption and extensive metabolism. The present study aims at evaluating the capability of self-emulsifying drug delivery systems (SEDDS) to enhance resveratrol permeation across rat intestine and to modulate its presystemic metabolism. For that purpose, semi-solid (SS) and liquid (L) SEDDS were prepared and dispersed in an aqueous buffer to produce nanoemulsions (NE). The jejunal absorptive transepithelial fluxes (Jms) of resveratrol elicited by these formulations (SS-NE and L-NE) and presystemic metabolization were determined on Ussing chambers. The absorptive fluxes through the intestinal epithelium from the nanoemulsions (Jms=20.5±3.1µgh-1cm-2 SS-NE; 28.9±2.9µgh-1cm-2 L-NE) were significantly increased compared to an ethanolic control solution (Jms=3.4±0.3µgh-1cm-2, p<0.05). No significant variations of conductance were observed after two hours of contact between the formulations and the mucosa. Simultaneously, the presystemic metabolization pattern was modified in the case of the nanoemulsions compared to the control solution. In conclusion, our data suggests that oil-in-water nanoemulsions prepared from SEDDS dispersions of medium-chain lipids could be promising formulations for enhancing oral delivery of resveratrol.

Administration of resveratrol: What formulation solutions to bioavailability limitations?

Resveratrol (3,5,4'-trihydroxystilbene), a naturally occurring polyphenol, has attracted considerable interest for its beneficial potentials for human health, which include anti-oxidant, anti-inflammatory, cardioprotective and anti-tumor activities. However, the in vivo biological effects of resveratrol appear strongly limited by its low bioavailability, which is a barrier to the development of therapeutic applications. In this context, an increasing number of recent studies have aimed at designing novel resveratrol formulations to overcome its poor solubility, limited stability, high metabolization and weak bioavailability. This review outlines physicochemical and pharmacokinetic limitations to resveratrol bioavailability, describes formulations tested for resveratrol administration, controlled release and targeting, and identifies future opportunities for resveratrol delivery.

Effect of apoE/ATP-containing liposomes on hepatic energy state.

BACKGROUND/AIMS: ATP-containing liposomes partially prevent ATP depletion in the cold-stored liver. As hepatocytes can specifically bind apoE, we investigated whether the addition of apoE to large (200 nm) ATP-containing liposomes increases their uptake by the liver and further improves hepatic energy stores. METHODS: Livers from fasted male Hartley guinea-pigs (231 +/- 3 g) were perfused for 90 min under our standard conditions (Control, n = 6) or after a single bolus addition of plain liposomes (Lip, n = 6), ATP (5 micromol)-containing liposomes (ATP-Lip, n = 6) or apoE/ATP-containing liposomes (0.8 or 8mg apoE/g phospholipids; apoE1-Lip and apoE10-Lip, respectively, n = 6 in each group). Liposome uptake and its impact on energy and nitrogen metabolism were studied. RESULTS: At its highest concentration, apoE significantly increased liposome uptake (apoE10-Lip: - 9.17 +/- 0.69 vs apoE1-Lip: - 6.18 +/- 0.44 vs ATP-Lip: - 6.40 +/- 0.88 nmol min(-1) g(-1) P < 0.05). This was associated with a significant increase in intrahepatic ATP (apoE10-Lip: 1033 +/- 137 vs apoE1-Lip: 811 +/- 98 and ATP-Lip: 648 +/- 36 nmol g(-1); P < 0.05), which was restored to its level in non-perfused livers. Hepatic viability and nitrogen metabolism were not affected. CONCLUSIONS: Hepatic ATP content being a key factor in the maintenance of liver graft function, apoE/ATP-containing liposomes should be useful in liver preservation for transplantation.

Poloxamer 407 as a thermogelling and adhesive polymer for rectal administration of short-chain fatty acids.

OBJECTIVES: The purpose of the study was to gel a rectal solution of short-chain fatty acids to decrease the loss of active materials in the colonic lumen and thereby optimize their absorption. METHODS: Five thermogels were prepared with poloxamer 407 at concentrations ranging from 17% to 20%. Their viscosities were measured at room temperature and 37 degrees C, and their gelling temperatures were determined. The adhesive properties of each gel were assessed in vitro at 37 degrees C. Short-chain fatty acid release was studied using Guyot cells. RESULTS: From the threshold concentration of 17.5%, the solutions, Newtonian at room temperature (50-80 mPa x s), gelled at 37 degrees C. The higher the concentration, the higher the viscosity (1750 to 49,000 mPa x s), the lower the gelling temperature (27.6 degrees C to 23.4 degrees C), and the stronger the work of adhesion (2.2 to 4.5 mJ). Short-chain fatty acid release from the 18% polymer gel was decreased by 60% compared to the rectal solution. CONCLUSION: The 18% poloxamer 407 concentration provided a solution that was liquid at room temperature, that gelled at 37 degrees C, possessed adhesive properties, and controlled short-chain fatty acid release.

Prevention of proteolysis in cold-stored rat liver by addition of amino acids to the preservation solution.

BACKGROUND: One process identified as detrimental in liver preservation is proteolysis. METHODS: We tested the effects of adding antiproteolytic amino acids (L-alanine, L-glutamine, L-histidine, L-leucine, L-methionine, L-phenylalanine, L-proline, L-tryptophan) to the preservation medium, in a model of reperfusion of 24 h cold-stored rat livers. RESULTS: During the preservation period, antiproteolytic amino acids inhibited the proteolysis observed in stored livers as shown by branched-chain amino acid fluxes, which switched from release to uptake. During reperfusion, cold storage of lives without the addition of antiproteolytic amino acids resulted in a decrease in the total amino acid and branched-chain amino acid uptake and a lower perfusion flow rate. The addition of antiproteolytic amino acids during liver storage resulted in the maintenance of total amino acid and branched-chain amino acid uptake and a significant improvement in the perfusion flow rate during reperfusion. CONCLUSIONS: The presence of antiproteolytic amino acids in the preservation medium might be of interest in improving hepatic graft viability in transplantation.

Deletion of hydroxyethylstarch from University of Wisconsin solution induces cell shrinkage and proteolysis during and after cold storage of rat liver.

Among the numerous components of the University of Wisconsin (UW) solution used for organ preservation, the usefulness of hydroxyethylstarch (HES), the colloido-osmotic support of this solution, is controversial. The aim of our study was to determine the influence of HES on hepatic metabolism and intracellular hydration state during hypothermic preservation and after reperfusion in a model of isolated perfused rat liver. Three groups of eight livers were perfused either immediately or after 18 hours of cold storage in a UW-based preservation solution with or without HES. Omission of HES results in 1) a stimulation of protein degradation shown by the marked increase in branched-chain amino acid (BCAA) release (211 +/- 55 vs. 87 +/- 28 nmol/min/g; P < .05, modified UW group vs. UW group), 2) an increase in oxygen consumption (81.7 +/- 4.8 vs. 61.5 +/- 5.0 micromol/h/g; P < .05), 3) a decrease in glucose production (2.3 +/- 0.6 vs. 5.0 +/- 0.6 micromol/min/g; P < .05), and 4) a reduction in intracellular volume (414 +/- 36 vs. 557 +/- 41 microL/g; P < .05). We conclude that HES plays an important role in liver preservation by limiting proteolysis, possibly through the observed preservation of cell volume.