Amacher D E
Drug Safety Evaluation, Pfizer Central Research, Groton, Connecticut, 06340, USA.
Regul Toxicol Pharmacol. 1998 Apr;27(2):119-30. doi: 10.1006/rtph.1998.1201.
During the preclinical, early clinical, late-stage clinical, and postmarketing phases of the pharmaceutical discovery and development process, one important aspect of drug safety assessment involves monitoring for possible drug-induced hepatic injury. Hepatic injuries vary in nature from direct, intrinsic effects that are observed in most recipients and more than one species to rare idiosyncratic responses seen only in a few clinical subjects. Histological types of injuries vary from hepatocellular to hepatobiliary with multiple cellular effects characteristic of each type. Of the various clinical laboratory markers for hepatic injury, serum transaminases, especially alanine aminotransferase (ALT), are the most universally important indicators for studies ranging from early preclinical animal testing to postmarketing patient monitoring. This review examines the characteristics of hepatic toxicity that result in serum ALT changes, the differences in the etiology of hepatic responses which govern when liver injury is most likely to be detected during the four phases of the drug discovery and development process, and those modulating factors which affect the utility of ALT as a dependable marker of hepatic injury in clinical populations. The paper concludes with a summary of some ancillary methods for early preclinical screening such as in vitro metabolism and toxicity assays, gene and protein expression analysis, and some strategies for enhancing the probability for the early detection of idiosyncratic hepatotoxic responses which are infrequent but significant factors in the safety assessment process.
在药物研发过程的临床前、早期临床、晚期临床和上市后阶段，药物安全性评估的一个重要方面是监测可能的药物性肝损伤。肝损伤的性质各不相同，从大多数接受者和多个物种中观察到的直接、内在效应，到仅在少数临床受试者中出现的罕见特异质性反应。损伤的组织学类型从肝细胞型到肝胆型不等，每种类型都有多种细胞效应。在各种肝损伤临床实验室指标中，血清转氨酶，尤其是丙氨酸转氨酶（ALT），是从临床前动物早期试验到上市后患者监测等各类研究中最重要的通用指标。本综述探讨了导致血清ALT变化的肝毒性特征、在药物研发过程的四个阶段中决定何时最有可能检测到肝损伤的肝反应病因差异，以及影响ALT作为临床人群肝损伤可靠标志物效用的调节因素。本文最后总结了一些临床前早期筛查的辅助方法，如体外代谢和毒性试验、基因和蛋白质表达分析，以及一些提高特异质性肝毒性反应早期检测概率的策略，这些反应虽不常见，但在安全性评估过程中是重要因素。
