Powis G
Drug Metab Rev. 1983;14(6):1145-63. doi: 10.3109/03602538308991425.
Dose-dependent metabolism is seen for a number of anticancer drugs, and they provide examples of several different types of dose-dependent metabolic processes. Arabinosyl cytosine and 5-fluorouracil are drugs whose catabolism is saturated at high doses. Therapeutic response to both drugs has been linked to plasma concentration of parent compound, and a nonlinear dose-response relationships might exist at high doses. L-Alanosine also appears to exhibit saturable metabolism at high doses, and this might be responsible for the rapid onset of L-alanosine toxicity as the dose is increased. Isophosphamide is a drug which requires metabolic activation to exert its biological effect, and saturation of metabolism seen at high dose could lead to a plateau in the dose-response relationship. Thymidine exhibits saturation of metabolism at high doses due in part to product inhibition of metabolism. Product inhibition of metabolism has also been suggested for arabinosyl cytosine. Plasma elimination of thymidine and possible elimination of 6-diazo-5-oxo-L-norleucine exhibit characteristics of a dose-dependent "memory" effect. Dose-dependent metabolism of methotrexate is unusual in that formation of the presumed toxic metabolite increases with increase in dose and is associated with a qualitative change in the pattern of drug toxicity at high compared to low doses of drug. The relationship between dose and toxicity of drugs and other foreign compounds is poorly understood in man. Anticancer drugs are one of the few classes of compounds where the relationship of toxicity to dose is reasonably well documented in human subjects. Saturation of metabolism leading to dose-dependent pharmacokinetics occurs with several anticancer drugs, and different types of dose-dependent metabolism have been covered in this review. An attempt has been made to show how dose-dependent metabolism of anticancer drugs might relate to their toxicity. Principles of dose-dependent toxicity seen with anticancer drugs might usefully be applied to other classes of compounds, particularly compounds exhibiting cytotoxicity but also other forms of toxicity. Dose-dependent metabolism could also be important in determining the therapeutic effect of anticancer drugs, and application of principles of dose-dependent metabolism to the development of new chemotherapeutic regimens migh lead to more effective cancer chemotherapy.
许多抗癌药物都存在剂量依赖性代谢，它们展示了几种不同类型的剂量依赖性代谢过程。阿糖胞苷和5-氟尿嘧啶是其分解代谢在高剂量时会饱和的药物。这两种药物的治疗反应都与母体化合物的血浆浓度有关，在高剂量时可能存在非线性剂量反应关系。L-丙氨酸也似乎在高剂量时表现出饱和代谢，这可能是随着剂量增加L-丙氨酸毒性迅速出现的原因。异环磷酰胺是一种需要代谢激活才能发挥其生物学效应的药物，高剂量时出现的代谢饱和可能导致剂量反应关系出现平台期。胸苷在高剂量时表现出代谢饱和，部分原因是产物对代谢的抑制作用。阿糖胞苷也有人提出存在产物对代谢的抑制作用。胸苷的血浆消除以及6-重氮-5-氧代-L-正亮氨酸可能的消除表现出剂量依赖性“记忆”效应的特征。甲氨蝶呤的剂量依赖性代谢不同寻常之处在于，假定的有毒代谢产物的形成随着剂量增加而增加，并且与高剂量药物相比低剂量药物时药物毒性模式的定性变化有关。在人体中，药物及其他外来化合物的剂量与毒性之间的关系了解甚少。抗癌药物是为数不多的几类化合物中，其毒性与剂量的关系在人体受试者中有较为充分记录的一类。几种抗癌药物会出现导致剂量依赖性药代动力学的代谢饱和，本综述涵盖了不同类型的剂量依赖性代谢。已尝试展示抗癌药物的剂量依赖性代谢如何与其毒性相关。抗癌药物所见的剂量依赖性毒性原理可能有益地应用于其他类化合物，特别是表现出细胞毒性但也有其他形式毒性的化合物。剂量依赖性代谢在确定抗癌药物的治疗效果方面也可能很重要，将剂量依赖性代谢原理应用于新化疗方案的开发可能会带来更有效的癌症化疗。
