Pharmacogenomic associations of cyclophosphamide pharmacokinetic candidate genes with 4hydroxycyclophosphamide formation in children with Cancer.

IF 2.7 4区 医学 Q3 ONCOLOGY Cancer Chemotherapy and Pharmacology Pub Date : 2024-10-01 Epub Date: 2024-07-30 DOI:10.1007/s00280-024-04703-2
Sandi L Navarro, Navin Pinto, Douglas S Hawkins, Julie R Park, Saam Dilmaghani, Christine Rimorin, Michelle Wurscher, Jeannine S McCune
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Abstract

Purpose: 4-hydroxycyclophosphamide (4HCY) is the principal precursor to the cytotoxic metabolite of cyclophosphamide (CY), which is often used as first-line treatment of children with cancer. There is conflicting data regarding the relationship between CY efficacy, toxicity, and pharmacokinetics with the genes encoding proteins involved in 4HCY pharmacokinetics, specifically its formation and elimination.

Methods: We evaluated germline pharmacogenetics in children with various malignancies receiving their first CY dose. Using linear regression, we analyzed the associations between two pharmacokinetic outcomes - how fast a child cleared CY (i.e., CY clearance) and the ratio of the 4HCY/CY exposure, specifically area under the plasma concentration-time curve (AUC), and 372 single nucleotide polymorphisms (SNP) in 14 drug-metabolizing transporters or enzymes involved in 4HCY formation or elimination.

Results: Age was associated with the ratio of 4HCY/CY AUC (P = 0.004); Chemotherapy regimen was associated with CY clearance (P = 0.003). No SNPs were associated with CY clearance or the ratio of 4HCY/CY AUC after controlling for a false discovery rate.

Conclusion: Age and chemotherapy regimen, but not germline pharmacogenomics, were associated with CY clearance or the ratio of 4HCY/CY AUC. Other methods, such as metabolomics or lipidomics, should be explored.

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儿童癌症患者环磷酰胺药代动力学候选基因与 4hydroxycyclophosphamide 形成的药物基因组学关联。
目的:4-羟基环磷酰胺(4HCY)是环磷酰胺(CY)细胞毒性代谢产物的主要前体,常用于儿童癌症的一线治疗。关于环磷酰胺的疗效、毒性和药代动力学与编码参与 4HCY 药代动力学(特别是其形成和消除)的蛋白质的基因之间的关系,有相互矛盾的数据:我们对首次服用 CY 的各种恶性肿瘤患儿的种系药物遗传学进行了评估。采用线性回归法,我们分析了两种药代动力学结果--儿童清除 CY 的速度(即 CY 清除率)和 4HCY/CY 暴露比值(即血浆浓度-时间曲线下面积(AUC))--与 14 种参与 4HCY 形成或清除的药物代谢转运体或酶中的 372 个单核苷酸多态性(SNP)之间的关联:结果:年龄与 4HCY/CY AUC 的比值相关(P = 0.004);化疗方案与 CY 清除率相关(P = 0.003)。在控制虚假发现率后,没有SNP与CY清除率或4HCY/CY AUC比率相关:结论:年龄和化疗方案与CY清除率或4HCY/CY AUC比值有关,但与种系药物基因组学无关。应探索其他方法,如代谢组学或脂质组学。
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来源期刊
CiteScore
6.10
自引率
3.30%
发文量
116
审稿时长
2.5 months
期刊介绍: Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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