Department of Pharmacy, Uppsala University, Box 580, 751 23 Uppsala, Sweden.
Department of Pharmacy, Uppsala University, Box 580, 751 23 Uppsala, Sweden.
Eur J Pharm Biopharm. 2019 Sep;142:364-376. doi: 10.1016/j.ejpb.2019.07.005. Epub 2019 Jul 5.
Intestinal permeability is a key biopharmaceutical variable in pharmaceutical research and development, and regulatory assessment. In situ rat models are often used to predict the corresponding human intestinal permeability data. The rat single-pass intestinal perfusion (SPIP) and intestinal closed loop (ICL) models are commonly applied. The primary objective of this study was to collect, summarize, and evaluate all the available intestinal permeability data for drugs that have been obtained using these two in-situ rat models. The permeability data were also investigated for variability between the experimental designs. The literature survey found 635 permeability determinations for 90 drugs. The studies were performed on the jejunum (n = 284), whole small intestine (n = 111), colon (n = 108), ileum (n = 101), and duodenum (n = 30). All the SPIP (n = 484) and ICL (n = 147) permeability values were summarized in an easily accessible database. There was wide variability in the intestinal permeability to each drug between studies, which was unrelated to the permeability class of the drug. There was no relationship between rat intestinal permeability and luminal pH, luminal drug concentration, rat strain, experimental method, or intestinal region. There was, however, a correlation between permeability values determined in the same laboratory. This report showed that the SPIP and ICL methods are important in situ models for understanding and predicting intestinal drug absorption. However, conclusions based on permeability values sourced from different laboratories may not be reliable. Because each permeability study is unique and because between- and even within-laboratory variability can be substantial, data from individual studies should preferably be interpreted separately.
肠通透性是药物研发和监管评估中的一个关键的生物制药变量。原位大鼠模型通常用于预测相应的人体肠通透性数据。大鼠单次肠灌流（SPIP）和肠闭合环（ICL）模型通常被应用。本研究的主要目的是收集、总结和评估所有使用这两种原位大鼠模型获得的药物肠通透性数据，并对实验设计之间的变异性进行研究。文献调查发现，有 90 种药物的 635 个通透性测定值。这些研究是在空肠（n=284）、整个小肠（n=111）、结肠（n=108）、回肠（n=101）和十二指肠（n=30）上进行的。所有 SPIP（n=484）和 ICL（n=147）的通透性值都被总结在一个易于访问的数据库中。在研究之间，每种药物的肠通透性存在很大的变异性，与药物的通透性类别无关。大鼠肠通透性与腔内腔内 pH 值、腔内腔内药物浓度、大鼠品系、实验方法或肠区无关。然而，在同一实验室中确定的通透性值之间存在相关性。本报告表明，SPIP 和 ICL 方法是理解和预测肠道药物吸收的重要原位模型。然而，基于来自不同实验室的通透性值得出的结论可能不可靠。因为每个通透性研究都是独特的，并且在实验室之间甚至实验室内部都可能存在很大的变异性，所以最好单独解释来自个别研究的数据。
