Department of Pharmacy, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Department of Hematology/Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
J Pharm Biomed Anal. 2023 Sep 20;234:115578. doi: 10.1016/j.jpba.2023.115578. Epub 2023 Jul 13.
Vincristine (VCR) is a vital component in numerous treatment regimens for pediatric blood cancer. VCR-induced peripheral neuropathy (VIPN) represents a type of VCR toxicity influenced by multiple factors, including age, race, genetic traits, dosage, interactions, and administration regimen. However, the dose-response relationship of VIPN remains elusive. VCR is primarily metabolized by cytochrome P450 (CYP) 3 A to generate the major metabolite M1. To date, there is a lack of literature documenting the pharmacokinetics (PK) characteristics of VCR and M1 in Chinese children within a 96 h timeframe. To address the gap, a developed LC-MS/MS method was successfully employed in the PK study of VCR and M1 in Chinese pediatric acute lymphoblastic leukemia (ALL) patients. M1 was obtained through in vitro metabolism experiments, and mixed plasma samples of M1 and VCR were prepared. Plasma samples were pre-processed using the solid-phase extraction (SPE) technique. Samples were loaded into ProElut C18 Cartridges, washed with 5% methanol aqueous solution, and eluted with methanol. The eluent was concentrated and reconstituted for liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. The standard calibration curves for VCR and M1 were 0.1-50 ng/mL and 0.05-5 ng/mL, respectively, with linear coefficients exceeding 0.99. Accuracy and precision of quality control (QC) samples fell within 115%. The analytical approach satisfied the quantitative demands for VCR and M1 in plasma samples within 96 h. VCR was metabolized to M1 at a relatively constant proportion (5.37%-18.06%) of VCR in vivo. No significant differences were observed in PK parameters of VCR in Chinese children compared to other countries and races. Further investigation is required to identify the key factors influencing VIPN in Chinese children.
长春新碱（VCR）是治疗小儿血液癌的多种治疗方案中的重要组成部分。长春新碱诱导的周围神经病变（VIPN）是一种长春新碱毒性，受多种因素影响，包括年龄、种族、遗传特征、剂量、相互作用和给药方案。然而，VIPN 的剂量反应关系仍然难以捉摸。长春新碱主要由细胞色素 P450（CYP）3A 代谢生成主要代谢物 M1。迄今为止，尚无文献记录在中国儿童中 96 小时内长春新碱和 M1 的药代动力学（PK）特征。为了解决这一差距，成功地将开发的 LC-MS/MS 方法应用于中国小儿急性淋巴细胞白血病（ALL）患者中长春新碱和 M1 的 PK 研究。M1 通过体外代谢实验获得，混合了 M1 和长春新碱的血浆样品。使用固相萃取（SPE）技术对血浆样品进行预处理。将样品加载到 ProElut C18 提取柱上，用 5%甲醇水溶液洗涤，然后用甲醇洗脱。洗脱液浓缩后，用于液相色谱-串联质谱（LC-MS/MS）分析。长春新碱和 M1 的标准校准曲线分别为 0.1-50ng/mL 和 0.05-5ng/mL，线性系数超过 0.99。质量控制（QC）样品的准确度和精密度在 115%以内。该分析方法满足了 96 小时内血浆样品中长春新碱和 M1 的定量要求。长春新碱在体内以相对恒定的比例（5.37%-18.06%）代谢为 M1。与其他国家和种族相比，中国儿童长春新碱的 PK 参数无显著差异。需要进一步研究确定影响中国儿童 VIPN 的关键因素。
