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

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 Cmax 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.