Kalgutkar Amit S, Dalvie Deepak K, O'Donnell John P, Taylor Timothy J, Sahakian Diana C
Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, Groton, CT 06340, USA.
Curr Drug Metab. 2002 Aug;3(4):379-424. doi: 10.2174/1389200023337360.
The unexpected occurrence of idiosyncratic drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use or failure to release/withdrawal. This leads to considerable uncertainty in drug development and has led to attempts to try to predict a drug's potential to cause such reactions. The biotransformation of relatively inert drugs to highly reactive metabolites, commonly referred to as "bioactivation", is now recognized to be an obligatory step in several kinds of drug-induced adverse reactions. Reactive metabolites can be formed by most, if not all, of the enzymes that are involved in drug metabolism. A major theme explored in this review includes the diversity of oxidative bioactivation reactions on nitrogen-containing xenobiotics including drugs. A variety of Phase I enzymes including P450, MAO, and peroxidases bioactivate nitrogen-containing xenobiotics via direct oxidations on the nitrogen atom leading to reactive intermediates or by oxidation at an alternate site in the molecule; for the metabolite to be reactive via the latter sequence nitrogen participation in required. Examples of direct oxidations on nitrogen include the N-oxidation of aromatic amines (e.g. procainamide), single electron N-oxidation of imides (e.g. phenytoin), or alpha-carbon oxidations of arylalkyl- or alkylamines (e.g. mianserin), to reactive nitroso, nitrogen free radical and iminium species, respectively. Examples of indirect bioactivation are highlighted with aromatic amines (e.g. diclofenac) that undergo p-hydroxylation resulting in the formation of p-aminophenols, two-electron oxidation of which results in the formation of reactive quinoneimines. Potential strategies that could be utilized in the screening of novel bioactivation pathways are also discussed.
在临床试验后期或药物上市后意外发生的特异质药物反应，可能导致其使用受到严格限制或无法上市/撤市。这给药物研发带来了极大的不确定性，促使人们尝试预测药物引发此类反应的可能性。相对惰性的药物转化为高活性代谢物，通常称为“生物活化”，现已被认为是几种药物诱导的不良反应中的必要步骤。大多数（如果不是全部）参与药物代谢的酶都能形成反应性代谢物。本综述探讨的一个主要主题包括含氮外来化合物（包括药物）氧化生物活化反应的多样性。多种I相酶，包括细胞色素P450、单胺氧化酶和过氧化物酶，通过对氮原子的直接氧化导致反应性中间体的形成，或通过分子中其他位点的氧化，使含氮外来化合物发生生物活化；要使代谢物通过后一种途径具有反应性，则需要氮的参与。氮直接氧化的例子包括芳香胺的N-氧化（如普鲁卡因酰胺）、酰亚胺的单电子N-氧化（如苯妥英）或芳基烷基胺或烷基胺的α-碳氧化（如米安色林），分别生成反应性亚硝基、氮自由基和亚胺离子。间接生物活化的例子以芳香胺（如双氯芬酸）为例，其进行对羟基化反应生成对氨基酚，后者的双电子氧化导致反应性醌亚胺的形成。本文还讨论了可用于筛选新型生物活化途径的潜在策略。
