W L Chiou1, C Ma, S M Chung, T C Wu, H Y Jeong. 1. Department of Pharmaceutics and Pharmacodynamics, College of Pharmacy, University of Illinois at Chicago, 60612, USA.
Abstract
OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.
OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.
Authors: Gary W Caldwell; John A Masucci; Zhengyin Yan; William Hageman Journal: Eur J Drug Metab Pharmacokinet Date: 2004 Apr-Jun Impact factor: 2.441