Thormann U, Hänggi R, Kreuter M, Imanidis G
Institute of Pharma Technology, School of Life Sciences, University of Applied Sciences Northwestern Switzerland, Muttenz, Switzerland; Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Eur J Pharm Sci. 2015 Apr 5;70:92-106. doi: 10.1016/j.ejps.2014.11.011. Epub 2014 Dec 2.
The purpose of this work was to investigate the role of bioconjugation and carrier mediated efflux of conjugation products in the absorption mechanism of the sesquiterpene lactone nobilin in the Caco-2 model in vitro and to elucidate the impact of the extract of Chamomillae romanae flos and its ingredients on absorption. Transport experiments with inhibitors of P-gp, BCRP, and MRPs were performed to detect efflux and its connection to bioconversion and the effect of different ingredients of the plant extract on absorption processes was determined. Permeability, transport and bioconversion parameter values were deduced by kinetic multi-compartment modeling. Nobilin exhibited high permeability, low relative absorption and fast bioconversion producing glucuronide, cysteine conjugate, and glutathione conjugate that were transported by P-gp (the first two), apical MRP2 and basal MRP3 and possibly MRP1 out of the cell. Inhibition of efflux resulted in diminished bioconjugation and improved absorption. The extract increased the relative fraction absorbed primarily by directly inhibiting bioconversion, and by reducing efflux. Individual extract ingredients could only partly explain this effect. Extensive bioconversion, hence, limited absorption of nobilin in the Caco-2 model and the interplay between conjugation and efflux was shown to provide a possible mechanism for absorption increase. Plant extract increased absorption by this mechanism in addition to metabolic enzyme inhibition.
本研究旨在探讨生物共轭作用以及共轭产物的载体介导外排在倍半萜内酯诺比林体外Caco-2模型吸收机制中的作用，并阐明罗马洋甘菊提取物及其成分对吸收的影响。进行了使用P-糖蛋白（P-gp）、乳腺癌耐药蛋白（BCRP）和多药耐药相关蛋白（MRP）抑制剂的转运实验，以检测外排及其与生物转化的联系，并确定植物提取物不同成分对吸收过程的影响。通过动力学多室模型推导渗透率、转运和生物转化参数值。诺比林表现出高渗透性、低相对吸收率和快速生物转化，产生葡萄糖醛酸苷、半胱氨酸共轭物和谷胱甘肽共轭物，这些共轭物由P-gp（前两者）、顶端MRP2和基底MRP3以及可能的MRP1转运出细胞。外排抑制导致生物共轭作用减弱和吸收改善。提取物主要通过直接抑制生物转化和减少外排来增加吸收相对分数。单个提取物成分只能部分解释这种效应。因此，广泛的生物转化限制了诺比林在Caco-2模型中的吸收，并且共轭作用和外排之间的相互作用被证明是吸收增加的一种可能机制。植物提取物除了抑制代谢酶外，还通过这种机制增加吸收。
