Ting Yuwen, Jiang Yike, Lan Yaqi, Xia Chunxin, Lin Zhenyu, Rogers Michael A, Huang Qingrong
†Department of Food Science, Rutgers University, 65 Dudley Road, New Brunswick, New Jersey 08901, United States.
Mol Pharm. 2015 Jul 6;12(7):2229-36. doi: 10.1021/mp5007322. Epub 2015 May 28.
The oral bioavailability of hydrophobic compound is usually limited by the poor aqueous solubility in the gastrointestinal (GI) tract. Various oral formulations were developed to enhance the systemic concentration of such molecules. Moreover, compounds with high melting temperature that appear as insoluble crystals imposed a great challenge to the development of oral vehicle. Polymethoxyflavone, an emerging category of bioactive compounds with potent therapeutic efficacies, were characterized as having a hydrophobic and highly crystalline chemical structure. To enhance the oral dosing efficiency of polymethoxyflavone, a viscoelastic emulsion system with a high static viscosity was developed and optimized using tangeretin, one of the most abundant polymethoxyflavones found in natural sources, as a modeling compound. In the present study, different in vitro and in vivo models were used to mechanistically evaluate the effect of emulsification on oral bioavailability of tangeretin. In vitro lipolysis revealed that emulsified tangeretin was digested and became bioaccessible much faster than unprocessed tangeretin oil suspension. By simulating the entire human GI tract, TNO's gastrointestinal model (TIM-1) is a valuable tool to mechanistically study the effect of emulsification on the digestion events that lead to a better oral bioavailability of tangeretin. TIM-1 result indicated that tangeretin was absorbed in the upper GI tract. Thus, a higher oral bioavailability can be expected if the compound becomes bioaccessible in the intestinal lumen soon after dosing. In vivo pharmacokinetics analysis on mice again confirmed that the oral bioavailability of tangeretin increased 2.3 fold when incorporated in the viscoelastic emulsion than unformulated oil suspension. By using the combination of in vitro and in vivo models introduced in this work, the mechanism that underlie the effect of viscoelastic emulsion on the oral bioavailability of tangeretin was well-elucidated.
疏水性化合物的口服生物利用度通常受到其在胃肠道（GI）中水溶性差的限制。人们开发了各种口服制剂来提高此类分子的全身浓度。此外，具有高熔点且以不溶性晶体形式存在的化合物对口服载体的开发构成了巨大挑战。聚甲氧基黄酮是一类具有强大治疗功效的新兴生物活性化合物，其化学结构具有疏水性和高度结晶性。为了提高聚甲氧基黄酮的口服给药效率，以天然来源中含量最丰富的聚甲氧基黄酮之一橘皮素为模型化合物，开发并优化了一种具有高静态粘度弹性的乳液体系。在本研究中，使用了不同的体外和体内模型来从机制上评估乳化对橘皮素口服生物利用度的影响。体外脂解实验表明，乳化后的橘皮素比未处理的橘皮素油悬浮液消化得更快，生物可及性也更高。通过模拟整个人体胃肠道，TNO的胃肠道模型（TIM-1）是从机制上研究乳化对导致橘皮素口服生物利用度提高的消化过程影响的有价值工具。TIM-1实验结果表明，橘皮素在上消化道被吸收。因此，如果该化合物在给药后能很快在肠腔中具有生物可及性，那么有望获得更高的口服生物利用度。对小鼠的体内药代动力学分析再次证实，与未配制的油悬浮液相比，将橘皮素掺入弹性乳液中时，其口服生物利用度提高了2.3倍。通过使用本研究中引入的体外和体内模型相结合的方法，可以很好地阐明弹性乳液对橘皮素口服生物利用度影响的潜在机制。
