Involvement of the Inhibition of Intestinal Glucuronidation in Enhancing the Oral Bioavailability of Resveratrol by Labrasol Containing Nanoemulsions

Abstract

Nanoemulsions have been developed for the oral delivery of poorly bioavailable phenolic compounds that are sensitive to intestinal glucuronidation. However, little is known about the contribution of UDP-glucuronosyltransferase (UGT) inhibitory excipients in nanoemulsions toward the inhibition of intestinal glucuronidation and the consequent enhanced bioavailability. In this study, Labrasol but not poloxamer 188 (F68) was found to inhibit the glucuronidation of resveratrol (RES), a model phenolic compound, in an inhibition assay with rat microsomes. Subsequently, two nanoemulsions, Lab-N and F68-N, were prepared with similar particle size distribution, zeta potentials, and entrapment efficiency by coemulsifying with Labrasol or F68, respectively. Although Lab-N exhibited inferior or comparable profiles of in vitro release, cellular uptake in Caco-2 cells, and lymphatic transport in rats to F68-N, the in vitro absorption study with everted sacs suggested that Labrasol containing formulations significantly and dose-dependently increased the transport of RES relative to free RES or F68-N by decreasing the amount of permeated metabolite, RES-3-glucuronide (RES-G). The in vivo pharmacokinetic experiments indicated that Lab-N exhibited increments in the maximum plasma concentration and the bioavailability of RES by 1098% and 560%, respectively, and significant decreases in those of RES-G, compared to F68-N. The overall results demonstrated that the improved oral bioavailability of RES by Lab-N was mainly attributable to the inhibition of intestinal glucuronidation by the presence of UGT inhibitory excipient.

Improved systemic delivery of insulin by condensed drug loading in a dimpled suppository

“…For avoiding the enzymatic barrier, however, the effect of Labrasol on enzymatic activity must be considered. It is reported that Labrasol inhibits intestinal UDP-glucuronyl transferase (33). Although the effect of Labrasol on the activities of insulin degrading enzymes in the intestine is not clear, the condensed Labrasol in a dimple may inhibit them.…”

Structural modification of resveratrol leads to increased anti-tumor activity, but causes profound changes in the mode of action

“…The latter involve liposomal formulations (Mukherjee et al, 2011) and nanoemulsions (Zhou et al, 2015), while lead structure optimization focused on higher hydroxylated (Murias et al, 2004), halogenated (Lee et al, 2003), or methylated (Cardile et al, 2007) analogs of resveratrol.…”

Arylsulfatase B Mediates the Sulfonation-Transport Interplay in Human Embryonic Kidney 293 Cells Overexpressing Sulfotransferase 1A3

“…The present study and our previous one (Sun et al, 2015b) indicated that cellular conjugation is regulated by efflux transporters. Hence, the inhibition of both enzymes and transporters represented a novel and promising strategy to enhance the oral bioavailability of drugs undergoing extensive conjugation, although the inhibition of enzyme activity alone showed potential in enhancing resveratrol bioavailability (Zhou et al, 2015).…”