Pfizer Global Research and Development, Eastern Point Rd., Groton, CT 06340, USA.
Drug Metab Dispos. 2010 Oct;38(10):1900-5. doi: 10.1124/dmd.110.034876. Epub 2010 Jul 1.
Metabolism is one of the important determinants of the overall disposition of drugs, and the profile of metabolites can have an impact on efficacy and safety. Predicting which drug metabolites will be quantitatively predominant in humans has become increasingly important in the research and development of new drugs. In this study, a novel micropatterned hepatocyte coculture system was evaluated for its ability to generate human in vivo metabolites. Twenty-seven compounds of diverse chemical structure and subject to a range of drug biotransformation reactions were assessed for metabolite profiles in the micropatterned coculture system using pooled cryopreserved human hepatocytes. The ability of this system to generate metabolites that are >10% of dose in excreta or >10% of total drug-related material in circulation was assessed and compared to previously reported data obtained in human hepatocyte suspensions, liver S-9 fraction, and liver microsomes. The micropatterned coculture system was incubated for up to 7 days without a change in medium, which offered an ability to generate metabolites for slowly metabolized compounds. The micropatterned coculture system generated 82% of the excretory metabolites that exceed 10% of dose and 75% of the circulating metabolites that exceed 10% of total circulating drug-related material, exceeds the performance of hepatocyte suspension incubations and other in vitro systems. Phase 1 and phase 2 metabolites were generated, as well as metabolites that arise via two or more sequential reactions. These results suggest that this in vitro system offers the highest performance among in vitro metabolism systems to predict major human in vivo metabolites.
代谢是药物整体处置的重要决定因素之一，代谢产物的特征可能会影响疗效和安全性。预测哪些药物代谢产物将在人体中具有定量优势，在新药研发中变得越来越重要。在这项研究中，评估了一种新型微图案化肝细胞共培养系统，以评估其生成人体体内代谢物的能力。使用汇集的冷冻保存人肝细胞，评估了 27 种具有不同化学结构且受多种药物生物转化反应影响的化合物在微图案共培养系统中的代谢产物特征。评估了该系统生成排泄中超过 10%剂量或循环中超过 10%总药物相关物质的代谢产物的能力，并与先前在人肝细胞悬浮液、肝 S-9 级分和肝微粒体中获得的报告数据进行了比较。微图案共培养系统在不更换培养基的情况下孵育长达 7 天，这为代谢缓慢的化合物生成代谢物提供了能力。微图案共培养系统生成了 82%的排泄代谢产物，超过 10%的剂量，生成了 75%的循环代谢产物，超过 10%的总循环药物相关物质，超过了肝细胞悬浮液孵育和其他体外系统的性能。生成了 I 相和 II 相代谢产物，以及通过两个或更多连续反应生成的代谢产物。这些结果表明，与其他体外代谢系统相比，该体外系统在预测主要人体体内代谢物方面具有最高的性能。
