Morgan D G, Kelvin A S, Kinter L B, Fish C J, Kerns W D, Rhodes G
Department of Toxicology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
Toxicol Pathol. 1994 Mar-Apr;22(2):112-23. doi: 10.1177/019262339402200205.
Appropriate dosage selection is a key element in the design of toxicology studies and, hence, is the first step in the process of evaluating the safety of a new chemical or pharmaceutical agent. This demands careful consideration of exposure to the drug or chemical under investigation in relation to the pharmacological or toxicological effects it evokes in an experimental animal. Toxicokinetic data provide this perspective, but they should not be considered exclusively of other data which reflect the specific activity, potency, or metabolism of the drug or chemical in each individual test species. It is equally inappropriate to base dosage selection in toxicology studies exclusively on functional or morphological endpoints that cause effects outside the range which can be accommodated by homeostatic mechanisms and repair processes. Finally, extrapolation of toxicokinetic data across species lines can lead to serious miscalculations with respect to both dosage selection and the process of risk assessment. In each case, decisions should be based on the integration of toxicokinetic data with other measures and endpoints of biological and toxicological effect.
合适的剂量选择是毒理学研究设计中的关键要素，因此也是评估新化学物质或药物安全性过程的第一步。这需要仔细考虑受试药物或化学物质的暴露情况与其在实验动物中引发的药理或毒理效应之间的关系。毒代动力学数据提供了这一视角，但不应仅考虑这些数据，还应结合反映受试药物或化学物质在每个测试物种中的特定活性、效力或代谢情况的其他数据。在毒理学研究中仅基于超出体内稳态机制和修复过程所能承受范围而产生效应的功能或形态学终点来选择剂量同样不合适。最后，跨物种推导毒代动力学数据可能导致在剂量选择和风险评估过程中出现严重的计算错误。在每种情况下，决策都应基于毒代动力学数据与生物学和毒理学效应的其他测量指标及终点的综合考量。
