Win L Chiou1, Paul W Buehler. 1. Department of Pharmaceutics and Pharmacodynamics, College of Pharmacy, The University of Illinois at Chicago, 60612, USA. Chiou@uic.edu
Abstract
PURPOSE: To compare the oral absorption and bioavailability of numerous drugs with a wide variety of physicochemical and pharmacological properties between humans and monkeys and to explore potential reasons for the findings. METHODS: Data for fraction of dose absorbed (Fa) and oral absolute bioavailability (F) were obtained by an extensive Medline database search. Inclusion and exclusion criteria were the same as those reported in our previous studies. A total of 43 and 35 drugs were selected for Fa and F comparison, respectively. The time to reach peak concentration (t(max)), total clearance, and nonrenal clearance were evaluated for 15, 28, and 13 drugs, respectively. RESULTS: Fa values in monkeys were similar or identical to those in humans. Additionally, similar t(max) values were seen in monkeys and humans at comparable doses, thus indicating comparable absorption kinetics between the two species. Conversely, F values in monkeys were generally lower with coumarin being a marked exception. Both total and nonrenal clearances were evaluated and found to be generally greater in monkeys, supporting a generally higher first-pass metabolism and lower F in this species. This was also supported by published data suggesting greater in vitro hepatic drug metabolism for monkeys as compared to humans. CONCLUSIONS: Monkeys appear to be a good predictor of Fa in humans. However, a generally lower F makes monkeys a potentially poor predictor of human F. Higher reported metabolic clearances and hepatic enzyme activities in monkeys may account for this observation.
PURPOSE: To compare the oral absorption and bioavailability of numerous drugs with a wide variety of physicochemical and pharmacological properties between humans and monkeys and to explore potential reasons for the findings. METHODS: Data for fraction of dose absorbed (Fa) and oral absolute bioavailability (F) were obtained by an extensive Medline database search. Inclusion and exclusion criteria were the same as those reported in our previous studies. A total of 43 and 35 drugs were selected for Fa and F comparison, respectively. The time to reach peak concentration (t(max)), total clearance, and nonrenal clearance were evaluated for 15, 28, and 13 drugs, respectively. RESULTS: Fa values in monkeys were similar or identical to those in humans. Additionally, similar t(max) values were seen in monkeys and humans at comparable doses, thus indicating comparable absorption kinetics between the two species. Conversely, F values in monkeys were generally lower with coumarin being a marked exception. Both total and nonrenal clearances were evaluated and found to be generally greater in monkeys, supporting a generally higher first-pass metabolism and lower F in this species. This was also supported by published data suggesting greater in vitro hepatic drug metabolism for monkeys as compared to humans. CONCLUSIONS: Monkeys appear to be a good predictor of Fa in humans. However, a generally lower F makes monkeys a potentially poor predictor of human F. Higher reported metabolic clearances and hepatic enzyme activities in monkeys may account for this observation.
Authors: Xianhua Cao; Seth T Gibbs; Lanyan Fang; Heather A Miller; Christopher P Landowski; Ho-Chul Shin; Hans Lennernas; Yanqiang Zhong; Gordon L Amidon; Lawrence X Yu; Duxin Sun Journal: Pharm Res Date: 2006-08 Impact factor: 4.200
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