Akiyama Yoshiyuki, Matsumura Naoya, Ono Asami, Hayashi Shun, Funaki Satoko, Tamura Naomi, Kimoto Takahiro, Jiko Maiko, Haruna Yuka, Sarashina Akiko, Ishida Masahiro, Nishiyama Kotaro, Fushimi Masahiro, Kojima Yukiko, Fujita Takuya, Sugano Kiyohiko
Drug Metabolism & Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
Early Stage Oral Formulation Research & Development, Pharmaceutical Research & Development, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan.
Pharm Res. 2023 Feb;40(2):359-373. doi: 10.1007/s11095-022-03173-6. Epub 2022 Feb 15.
In drug discovery, rats are widely used for pharmacological and toxicological studies. We previously reported that a mechanism-based oral absorption model, the gastrointestinal unified theoretical framework (GUT framework), can appropriately predict the fraction of a dose absorbed (Fa) in humans and dogs. However, there are large species differences between humans and rats. The purpose of the present study was to evaluate the predictability of the GUT framework for rat Fa.
The Fa values of 20 model drugs (a total of 39 Fa data) were predicted in a bottom-up manner. Based on the literature survey, the bile acid concentration (C) and the intestinal fluid volume were set to 15 mM and 4 mL/kg, respectively, five and two times higher than in humans. LogP, pK, molecular weight, intrinsic solubility, bile micelle partition coefficients, and Caco-2 permeability were used as input data.
The Fa values were appropriately predicted for highly soluble drugs (absolute average fold error (AAFE) = 1.65, 18 Fa data) and poorly soluble drugs (AAFE = 1.57, 21 Fa data). When the species difference in C was ignored, Fa was over- and under-predicted for permeability and solubility limited cases, respectively. High C in rats reduces the free fraction of drug molecules available for epithelial membrane permeation while increasing the solubility of poorly soluble drugs.
The Fa values in rats were appropriately predicted by the GUT framework. This result would be of great help for a better understanding of species differences and model-informed preclinical formulation development.
在药物研发中，大鼠被广泛用于药理学和毒理学研究。我们之前报道过一种基于机制的口服吸收模型，即胃肠道统一理论框架（GUT框架），可以适当地预测人体和犬类的剂量吸收分数（Fa）。然而，人与大鼠之间存在很大的种属差异。本研究的目的是评估GUT框架对大鼠Fa的预测能力。
以自下而上的方式预测了20种模型药物的Fa值（共39个Fa数据）。基于文献调研，将胆汁酸浓度（C）和肠液体积分别设定为15 mM和4 mL/kg，分别是人体相应值的5倍和2倍。使用logP、pK、分子量、固有溶解度、胆汁微团分配系数和Caco-2通透性作为输入数据。
对于高溶解性药物（绝对平均倍数误差（AAFE）=1.65，18个Fa数据）和低溶解性药物（AAFE=1.57，21个Fa数据），Fa值得到了适当的预测。当忽略C的种属差异时，在通透性和溶解度受限的情况下，Fa分别被高估和低估。大鼠体内较高的C降低了可用于上皮膜渗透的药物分子的游离分数，同时增加了低溶解性药物的溶解度。
GUT框架能够适当预测大鼠的Fa值。这一结果将有助于更好地理解种属差异，并为基于模型的临床前制剂开发提供帮助。
