Holmstock Nico, De Bruyn Tom, Bevernage Jan, Annaert Pieter, Mols Raf, Tack Jan, Augustijns Patrick
Laboratory for Drug Delivery and Disposition, KU Leuven, Campus Gasthuisberg, O&N 2, Herestraat 49, Box 921, B-3000 Leuven, Belgium.
Department of Gastroenterology, University Hospitals Leuven, O&N, Herestraat 49, Box 701, B-3000 Leuven, Belgium.
Eur J Pharm Sci. 2013 Apr 11;49(1):27-32. doi: 10.1016/j.ejps.2013.01.012. Epub 2013 Feb 9.
Food can have a significant impact on the pharmacokinetics of orally administered drugs, as it may affect drug solubility as well as permeability. Since fed state conditions cannot easily be implemented in the presently available permeability tools, including the frequently used Caco-2 system, exploring food effects during drug development can be quite challenging. In this study, we investigated the effect of fasted and fed state conditions on the intestinal absorption of the HIV protease inhibitor indinavir using simulated and human intestinal fluids in the in situ intestinal perfusion technique in mice. Although the solubility of indinavir was 6-fold higher in fed state human intestinal fluids (FeHIF) as compared to fasted state HIF (FaHIF), the intestinal permeation of indinavir was 22-fold lower in FeHIF as compared to FaHIF. Dialysis experiments showed that only a small fraction of indinavir is accessible for absorption in FeHIF due to micellar entrapment, possibly explaining its low intestinal permeation. The presence of ritonavir, a known P-gp inhibitor, increased the intestinal permeation of indinavir by 2-fold in FaHIF, while there was no increase when using FeHIF. These data confirm that drug-food interactions form a complex interplay between solubility and permeability effects. The use of HIF in in situ intestinal perfusions holds great promise for biorelevant absorption evaluation as it allows to directly explore this complex solubility/permeability interplay on drug absorption.
食物对口服药物的药代动力学可能有显著影响，因为它可能会影响药物的溶解度和渗透性。由于在目前可用的渗透性研究工具中，包括常用的Caco-2系统，难以轻易实现进食状态条件，因此在药物研发过程中探索食物的影响颇具挑战性。在本研究中，我们使用模拟肠液和人肠液，采用原位肠灌注技术，在小鼠中研究了禁食和进食状态条件对HIV蛋白酶抑制剂茚地那韦肠道吸收的影响。尽管与禁食状态的人肠液（FaHIF）相比，茚地那韦在进食状态的人肠液（FeHIF）中的溶解度高6倍，但茚地那韦在FeHIF中的肠道渗透率比FaHIF低22倍。透析实验表明，由于胶束截留，在FeHIF中只有一小部分茚地那韦可用于吸收，这可能解释了其肠道渗透率较低的原因。已知的P-糖蛋白抑制剂利托那韦的存在，使茚地那韦在FaHIF中的肠道渗透率提高了2倍，而在使用FeHIF时则没有增加。这些数据证实，药物与食物的相互作用在溶解度和渗透性影响之间形成了复杂的相互作用。在原位肠灌注中使用人肠液对生物相关吸收评估具有很大的前景，因为它可以直接探索这种复杂的溶解度/渗透性相互作用对药物吸收的影响。
