Sodium Oleate-Based Nanoemulsion Enhances Oral Absorption of Chrysin through Inhibition of UGT-Mediated Metabolism

Abstract

Oral bioavailability of flavonoids (and many phenolic drugs) is severely limited by extensive first-pass glucuronidation. Here we aimed to determine the modulatory effects of commonly used pharmaceutical excipients (PEs) on UDP-glucuronosyltransferase (UGT) activities and to evaluate the potential of nanoemulsions containing a UGT-inhibitory PE for oral absorption enhancement of chrysin, a model flavonoid. The effects of PEs on glucuronidation were determined using tissue (liver and intestine) microsomes, expressed UGT1A1 enzyme, and UGT1A1-overexpressing HeLa cells. Nanoemulsions were prepared using a modified emulsification technique and subsequently characterized by particle size, zeta-potential, morphology, and in vitro drug release. Pharmacokinetic studies were performed with rats to assess the effects of nanoemulsions on the metabolism and pharmacokinetics of chrysin. Of 21 PEs, five (i.e., Brij 35, Brij 58, labrasol, sodium oleate, and Tween 20) significantly inhibited chrysin glucuronidation. Of note, sodium oleate was the most potent inhibitor of glucuronidation. Eight PEs including Tween 80 had no effects on glucuronidation of chrysin. The chrysin nanoemulsions prepared with sodium oleate (named SO-NE) were spherical or near-spherical (particle size, 83.2 nm; zeta-potential, -43.7 mV; entrapment efficiency, 89.5%). The reference nanoemulsions prepared with Tween 80 (T80-NE) were highly similar to SO-NE in terms of particle size, zeta-potential, and drug release. It was demonstrated in pharmacokinetic studies that SO-NE led to a 4.3-fold increase in systemic exposure of chrysin and a 3.5-fold increase in C value, whereas T80-NE did not cause any changes in chrysin pharmacokinetics. In conclusion, sodium oleate-based nanoemulsions greatly enhanced oral absorption of chrysin. Oral absorption enhancement of chrysin was attained through targeted inhibition of first-pass glucuronidation by sodium oleate.

Effects of Chrysin and Its Major Conjugated Metabolites Chrysin-7-Sulfate and Chrysin-7-Glucuronide on Cytochrome P450 Enzymes and on OATP, P-gp, BCRP, and MRP2 Transporters

“…Walle et al (2001) reported that after the oral administration of a 400-mg single dose of chrysin to healthy human subjects, peak plasma concentration of the parent compound was only 16-63 nM, whereas C7S appeared approximately at 400-800 nM concentrations in the circulation. In rodent experiments, peak plasma concentrations of C7S and C7G were also considerably higher than that of chrysin (Ge et al, 2015;Noh et al, 2016;Dong et al, 2017). In mice, the 20 mg/kg oral dose of chrysin caused 10, 130, and 160 nM peak plasma concentrations of chrysin, C7S and C7G, respectively (Ge et al, 2015).…”

Hydrous icaritin nanorods with excellent stability improves the in vitro and in vivo activity against breast cancer

“…It has been reported that most flavonoids are subject to phase II metabolism and the widely occurred phase II metabolism becomes one of the main reasons for the low oral bioavailability for flavonoids (Dong et al, 2017). Thus, SO, a strong phase II metabolism inhibitor (He et al, 2018), was added in the formulation of HICT NRs with the aim of improving the oral bioavailability of HICT.…”

Systemic delivery of the anticancer agent arenobufagin using polymeric nanomicelles

“…After 48-hour incubation, the cells were subjected to MTT assays as previously described. 25 Optical density measurements were performed at 570 nm using a Synergy HTX microplate reader (Biotek, Winooski, VT, USA). cellular uptake study Cellular uptake mechanism of ABG-PNs was determined using HepG2 cells (Cell Bank of Chinese Academy of Sciences).…”

“…At a low temperature, the adenosine triphosphate (ATP) output is limited due to the activity inhibition of energy-productive enzymes, resulting in a reduction of cellular uptake. 25,30 Endocytosis generally is a more efficient uptake process than others such as passive diffusion and carrier-mediated transport. 31,32 ABG-PNs showed an improved pharmacokinetic profile that was featured with an increase in AUC value and a decrease in body clearance ( Figure 6).…”