Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.
Department of Anatomy, School of Medicine, European University of Cyprus, Nicosia, Cyprus.
Front Endocrinol (Lausanne). 2023 May 24;14:1143835. doi: 10.3389/fendo.2023.1143835. eCollection 2023.
Accumulating clinical evidence indicates extensive inter-individual variations in the effectiveness and adverse effects of standard treatment protocols, which are largely attributed to the multifactorial regulation of the hepatic CYP-dependent drug metabolism that is connected with either transcriptional or post-translational modifications. Age and stress belong to the most important factors in CYP gene regulation. Alterations in neuroendocrine responses to stress, which are associated with modified hypothalamo-pituitary-adrenal axis function, usually accompany ageing. In this light, ageing followed by a decline of the functional integrity of organs, including liver, a failure in preserving homeostasis under stress, increased morbidity and susceptibility to stress, among others, holds a determinant role in the CYP-catalyzed drug metabolism and thus, in the outcome and toxicity of pharmacotherapy. Modifications in the drug metabolizing capacity of the liver with age have been reported and in particular, a decline in the activity of the main CYP isoforms in male senescent rats, indicating decreased metabolism and higher levels of the drug-substrates in their blood. These factors along with the restricted experience in the use of the most medicines in childhood and elderly, could explain at an extent the inter-individual variability in drug efficacy and toxicity outcomes, and underscore the necessity of designing the treatment protocols, accordingly.
越来越多的临床证据表明，标准治疗方案的疗效和不良反应在个体之间存在广泛差异，这主要归因于肝 CYP 依赖性药物代谢的多因素调节，与转录或翻译后修饰有关。年龄和应激是 CYP 基因调节的最重要因素之一。与下丘脑-垂体-肾上腺轴功能改变相关的神经内分泌对应激的反应改变，通常伴随着衰老。从这个角度来看，衰老伴随着器官（包括肝脏）功能完整性的下降、在应激下维持内稳态的失败、发病率增加以及对应激的易感性增加等，在 CYP 催化的药物代谢中起着决定性的作用，因此也影响药物治疗的结果和毒性。已经报道了年龄对肝脏药物代谢能力的改变，特别是雄性衰老大鼠中主要 CYP 同工酶活性的下降，表明代谢减少和其血液中药物底物水平升高。这些因素以及在儿童和老年人中使用大多数药物的经验有限，可以在一定程度上解释药物疗效和毒性结果的个体间变异性，并强调需要相应地设计治疗方案。
