Ono Pharmaceutical Co., Ltd., 3-3-1, Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
Ono Pharmaceutical Co., Ltd., 3-3-1, Sakurai, Shimamoto-cho, Mishima-gun, Osaka 618-8585, Japan.
J Pharm Sci. 2018 Sep;107(9):2489-2496. doi: 10.1016/j.xphs.2018.05.016. Epub 2018 Jun 1.
Dogs have been widely used to study the oral absorption of a drug in drug discovery. However, there has been no quantitative validation of using dogs to predict the fraction of oral dose absorbed (Fa) in humans (Fa) for poorly water-soluble drugs. Here, we report the results of using dogs for quantitative Fa prediction, focusing on poorly water-soluble free acid and neutral drugs. The Fa values of 4 acidic and 1 neutral proprietary compounds were measured in humans and dogs. Extensive literature survey was also performed to increase the number of Fa data. Fa and Fa in dogs (Fa) were then compared at equivalent body weight-normalized doses. In the case of neutral compounds, Fa was found to be similar to Fa. In the case of acidic compounds, Fa significantly overestimated Fa in most cases. A difference in intestinal pH was suggested as the main reason for this discrepancy. In conclusion, the use of dogs would not be appropriate to predict Fa for acidic compounds, but more work is required to know about neutral compounds.
狗已被广泛用于研究药物发现过程中药物的口腔吸收。然而，目前还没有定量验证使用狗来预测人体（Fa）中难溶性药物的口服剂量吸收率（Fa）的分数。在这里，我们报告了使用狗进行定量 Fa 预测的结果，重点是难溶性游离酸和中性药物。在人和狗中测量了 4 种酸性和 1 种中性专有化合物的 Fa 值。还进行了广泛的文献调查，以增加 Fa 数据的数量。然后在等效体重归一化剂量下比较了狗（Fa）中的 Fa 和 Fa。对于中性化合物，发现 Fa 与 Fa 相似。对于酸性化合物，在大多数情况下，Fa 显著高估了 Fa。肠道 pH 差异被认为是这种差异的主要原因。总之，对于酸性化合物，使用狗来预测 Fa 是不合适的，但还需要更多的工作来了解中性化合物。
