Abstract

1. Knowledge of inter-strain and inter-gender differences in drug metabolism studies is important for animal selection in pharmacokinetic and toxicological studies.

2. The effects of rat strain and gender in in vitro metabolism were investigated in Sprague Dawley (SD) and Wister Han (WH) rats based on the hepatocyte metabolic profiles of 14 small molecule drugs.

3. Similarities were found between the hepatocyte metabolic clearances of SD and WH strains, suggesting that only one strain can be confidently used for the evaluation of hepatic clearance. Neither strain of rat was preferable over the other to cover human metabolites. Higher similarities in metabolic pathways were found between the same gender than the same strain.

4. Differences in metabolite identities, metabolite formation rates and potential biotransformation pathways were observed between SD and WH rat strains. Eleven metabolites from six drugs were “disproportionally” formed between SD and WH rats.

5. The use of a specific rat strain model and gender for ADME and toxicity testing should, therefore, be carefully considered as metabolic profiles may differ, even though metabolic clearance was similar between SD and WH rats.

摘要

1. 药物代谢研究中有关品系间和性别间差异的知识对于药代动力学和毒理学研究中的动物选择非常重要。

2. 根据14种小分子药物的肝细胞代谢特征，在Sprague Dawley（SD）和Wister Han（WH）大鼠中研究了大鼠品系和性别对体外代谢的影响。

3. SD和WH菌株的肝细胞代谢清除率之间存在相似性，这表明只有一种菌株可以放心地用于评估肝清除率。两种大鼠中的任何一种都不能覆盖人的代谢产物。发现同一性别之间的代谢途径比同一菌株之间的相似性更高。

4. 在SD和WH大鼠品系之间观察到代谢物身份，代谢物形成速率和潜在的生物转化途径的差异。SD和WH大鼠之间“不成比例地”形成了六种药物的11种代谢产物。

5. 因此，应谨慎考虑使用特定的大鼠品系模型和性别进行ADME和毒性试验，因为即使SD和WH大鼠之间的代谢清除率相似，其代谢谱也可能不同。