Cyclophosphamide Pharmacogenomic Variation in Cancer Treatment and Its Effect on Bioactivation and Pharmacokinetics.

IF 2.1 Q3 PHARMACOLOGY & PHARMACY
Advances in Pharmacological and Pharmaceutical Sciences Pub Date : 2024-06-27 eCollection Date: 2024-01-01 DOI:10.1155/2024/4862706
Ibrahim El-Serafi, Sinclair Steele
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引用次数: 0

Abstract

Cyclophosphamide (Cy) is a prodrug that is mainly bioactivated by cytochrome P450 (CYP) 2B6 enzyme. Several other enzymes are also involved in its bioactivation and affect its kinetics. Previous studies have shown the effect of the enzymes' genetic polymorphisms on Cy kinetics and its clinical outcome. These results were controversial primarily because of the involvement of several interacting enzymes in the Cy metabolic pathway, which can also be affected by several clinical factors as well as other drug interactions. In this review article, we present the effect of CYP2B6 polymorphisms on Cy kinetics since it is the main bioactivating enzyme, as well as discussing all previously reported enzymes and clinical factors that can alter Cy efficacy. Additionally, we present explanations for key Cy side effects related to the nature and site of its bioactivation. Finally, we discuss the role of busulphan in conditioning regimens in the Cy metabolic pathway as a clinical example of drug-drug interactions involving several enzymes. By the end of this article, our aim is to have provided a comprehensive summary of Cy pharmacogenomics and the effect on its kinetics. The utility of these findings in the development of new strategies for Cy personalized patient dose adjustment will aid in the future optimization of patient specific Cy dosages and ultimately in improving clinical outcomes. In conclusion, CYP2B6 and several other enzyme polymorphisms can alter Cy kinetics and consequently the clinical outcomes. However, the precise quantification of Cy kinetics in any individual patient is complex as it is clearly under multifactorial genetic control. Additionally, other clinical factors such as the patient's age, diagnosis, concomitant medications, and clinical status should also be considered.

癌症治疗中的环磷酰胺药物基因组变异及其对生物活化和药物动力学的影响
环磷酰胺(Cy)是一种原药,主要由细胞色素 P450(CYP)2B6 酶进行生物活化。其他几种酶也参与其生物活化过程,并影响其动力学。以往的研究表明,酶的基因多态性对 Cy 动力学及其临床结果有影响。这些结果之所以存在争议,主要是因为 Cy 代谢途径中涉及多种相互作用的酶,而这些酶也会受到多种临床因素和其他药物相互作用的影响。在这篇综述文章中,我们介绍了 CYP2B6 多态性对 Cy 动力学的影响(因为它是主要的生物活化酶),并讨论了之前报道的所有可能改变 Cy 疗效的酶和临床因素。此外,我们还解释了与 Cy 生物活化的性质和部位有关的主要副作用。最后,我们讨论了丁苯酞在 Cy 代谢途径中的调理方案中的作用,以此作为涉及多种酶的药物间相互作用的临床实例。到本文结束时,我们的目标是全面总结 Cy 药物基因组学及其对动力学的影响。这些研究结果在开发 Cy 个性化患者剂量调整新策略方面的实用性将有助于未来优化特定患者的 Cy 剂量,并最终改善临床疗效。总之,CYP2B6 和其他几种酶的多态性可改变 Cy 的动力学,从而改变临床结果。然而,精确量化任何个体患者的 Cy 动力学是非常复杂的,因为它显然是受多因素遗传控制的。此外,还应考虑其他临床因素,如患者的年龄、诊断、伴随药物和临床状态。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
4.30
自引率
3.60%
发文量
0
审稿时长
17 weeks
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