Chiou W L, Ma C, Chung S M, Wu T C, Jeong H Y
Department of Pharmaceutics and Pharmacodynamics, College of Pharmacy, University of Illinois at Chicago, 60612, USA.
Int J Clin Pharmacol Ther. 2000 Nov;38(11):532-9. doi: 10.5414/cpp38532.
The main aim of this study was to provide a simple, pharmacokinetic rationale for great similarity in the extent (Fab) of gastrointestinal absorption of about 100 different, diverse compounds between human and the rat in linear dosing range, and to test the general applicability of a novel empirical method to correlate the non-linear Fab between the human and the rat by normalizing doses by body surface area (BSA) or body weight 0.67.
The mean small intestinal transit time (t) of 36 rats was estimated from the reported study, and this was used to compare with that in humans. The reported great similarity in apparent first-order absorption rate constants (k) of seven structurally diverse compounds between the two species were obtained. Extensive computer search was made and non-linear Fab data for the two species were obtained for chlorothiazide, acyclovir, miglitol and pafenolol.
The mean t for rats was estimated to be 3.32 h which is almost identical to that reported in humans. The great similarity in Fab between human and rat in linear absorption range can be rationalized by similar t and k between the two species. The markedly different Fab vs dose/kg of body weight profiles between human and rat for the four drugs showing dose-dependent Fab were found to collapse when doses were normalized by BW0.67.
For Fab not limited by the solubility problem, the great similarity in Fab between human and rat in linear absorption range can be rationalized by the similar t and k. For non-linear Fab drugs, great similarity in Fab can also be obtained between human and rat when doses are normalized by BSA or BW0.67. Regardless of absorption properties (active, passive or facilitated), similar Fab between the two species may be generally obtained when doses used in humans are about 5 to 7 times lower than that in rats. The above findings may be valuable in drug development.
本研究的主要目的是提供一个简单的药代动力学原理，以解释在直线剂量范围内，约100种不同化合物在人和大鼠胃肠道吸收程度（Fab）上的高度相似性，并通过按体表面积（BSA）或体重0.67对剂量进行归一化，来测试一种新的经验方法在关联人和大鼠之间非线性Fab方面的普遍适用性。
根据已发表的研究估算36只大鼠的平均小肠转运时间（t），并将其与人类的进行比较。获取了两种物种之间七种结构不同化合物的表观一级吸收速率常数（k）的高度相似性数据。进行了广泛的计算机检索，获得了氯噻嗪、阿昔洛韦、米格列醇和帕罗西汀这两种物种非线性Fab数据。
大鼠的平均t估计为3.32小时，与人类报道的几乎相同。人和大鼠在直线吸收范围内Fab的高度相似性可通过两种物种相似的t和k来解释。当按体重0.67对剂量进行归一化时，发现四种显示剂量依赖性Fab的药物在人和大鼠之间Fab与体重/千克剂量曲线明显不同的情况消失了。
对于不受溶解度问题限制的Fab，人和大鼠在直线吸收范围内Fab的高度相似性可通过相似的t和k来解释。对于非线性Fab药物，当按BSA或体重0.67对剂量进行归一化时，人和大鼠之间也可获得Fab的高度相似性。无论吸收特性（主动、被动或易化）如何，当人类使用的剂量比大鼠低约5至7倍时，两种物种之间通常可获得相似的Fab。上述发现可能对药物开发有价值。
