Department of Pharmacology & Clinical Pharmacology, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Environ Toxicol Pharmacol. 2006 Feb;21(2):184-90. doi: 10.1016/j.etap.2005.07.008. Epub 2005 Aug 2.
Animals provide a physiologically relevant system for evaluation of drug metabolism, but marked inter-species differences limit extrapolation to humans. Liver microsomes are used extensively as an in vitro human drug metabolising system, and with appropriate selection of parameters, such as substrate and enzyme concentrations, may predict both routes and rate of metabolism. However, variable enzyme expression between donors and overlapping substrate specificity influence reproducibility, hence recombinant human CYP enzymes expressed in human, yeast or insect cells have been developed. For complex metabolic profiles involving sequential or competing pathways, isolated hepatocytes and liver slices are of value. Altered enzyme activity and restricted availability constrain their use. Cryopreservation or culture increase availability, but changes in enzyme activity remain a constraint. To date, human in vitro systems do not predict all aspects of drug metabolism, thus a combination of in vivo animal and in vitro human studies will be required for the foreseeable future.
动物为评估药物代谢提供了一种具有生理相关性的系统，但明显的种间差异限制了向人类的推断。肝微粒体广泛用作体外人类药物代谢系统，并且通过适当选择参数，如底物和酶浓度，可以预测代谢途径和速率。然而，供体之间的酶表达变化和重叠的底物特异性会影响重现性，因此已开发出在人、酵母或昆虫细胞中表达的重组人 CYP 酶。对于涉及顺序或竞争途径的复杂代谢谱，分离的肝细胞和肝切片具有价值。改变的酶活性和有限的可用性限制了它们的使用。冷冻保存或培养增加了可用性，但酶活性的变化仍然是一个限制。迄今为止，人类体外系统并不能预测药物代谢的所有方面，因此在可预见的未来，需要将体内动物和体外人类研究结合起来。
