Khalil Hadeel A, Belal Tarek S, El-Yazbi Ahmed F, Hamdy Dalia A
Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Alexandria University, 1 El Khartoum Square, Alexandria, 21521, Egypt.
Department of Pharmacology & Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.
Lipids Health Dis. 2016 Sep 9;15(1):152. doi: 10.1186/s12944-016-0318-0.
Vincristine (VCR), an antineoplastic agent, is a key component in the treatment of acute lymphoblastic leukemia, lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilms' tumor diseases. Recently, high incidence of hyperlipidemia was reported to be associated with allogenic hematopoietic stem cell transplantation and VCR/L-asparaginase therapy. The aim of this study is to test the effects of incremental increase in lipoproteins levels on vincristine disposition in rat.
To study VCR pharmacokinetics and protein binding, rats (n = 25) were assigned to three groups, normal lipidemic (NL), intermediate (IHL) and extreme hyperlipidemic (HL). Hyperlipidemia was induced by ip injection of (1 g/Kg) poloxamer 407 in rats. Serial blood samples were collected using the pre-inserted jugular vein cannula for 72 h post VCR (0.15 mg/Kg) i.v. dose. VCR unbound fractions in NL, IHL and HL plasma were determined using ultrafiltration kits.
VCR demonstrated a rapid distribution phase (6-8 h) followed by a slower elimination phase with a mean elimination t½ of ~ 14 h. VCR exhibited moderate binding to plasma proteins ~ 83 %. It showed a relatively small Vc (~0.17 L/Kg) and a larger Vβ (1.53 L/Kg) indicating good tissue distribution. As the lipoproteins levels were increased, no significant changes were noted in VCR unbound fraction, plasma concentration, or volume of distribution indicating low affinity to lipoprotein binding. Induced HL also did not affect VCR elimination where similar VCR AUC0-∞, Cl and elimination phase t½ were reported along the different lipemic groups.
Incremental increase in lipoprotein levels resulted in no significant effect on VCR disposition as such ALL malignant lymphoma and allogenic hematopoietic stem cell transplantation patients need not to worry about HL-VCR interaction. Whether, HL can potentiate another drug-drug or drug-disease interaction involving VCR warrants further studying and monitoring to ensure therapeutic safety and efficiency.
长春新碱（VCR）是一种抗肿瘤药物，是治疗急性淋巴细胞白血病、淋巴瘤、横纹肌肉瘤、神经母细胞瘤和肾母细胞瘤等疾病的关键成分。最近，有报道称高脂血症的高发病率与异基因造血干细胞移植及VCR/L-天冬酰胺酶治疗有关。本研究的目的是测试脂蛋白水平的逐步升高对大鼠体内长春新碱处置的影响。
为研究VCR的药代动力学和蛋白结合情况，将大鼠（n = 25）分为三组，即正常血脂组（NL）、中度高脂血症组（IHL）和极度高脂血症组（HL）。通过腹腔注射（1 g/Kg）泊洛沙姆407诱导大鼠产生高脂血症。在静脉注射VCR（0.15 mg/Kg）后，使用预先插入的颈静脉插管连续采集血样72小时。使用超滤试剂盒测定NL、IHL和HL血浆中VCR的未结合分数。
VCR表现出快速分布期（6 - 8小时），随后是较慢的消除期，平均消除半衰期约为14小时。VCR与血浆蛋白的结合适中，约为83%。它显示出相对较小的中央室容积（Vc，约0.17 L/Kg）和较大的周边室容积（Vβ，1.53 L/Kg），表明其组织分布良好。随着脂蛋白水平的升高，VCR的未结合分数、血浆浓度或分布容积均未出现显著变化，表明其对脂蛋白结合的亲和力较低。诱导的HL也未影响VCR的消除，不同血脂组的VCR药时曲线下面积（AUC0 - ∞）、清除率（Cl）和消除期半衰期（t½）相似。
脂蛋白水平的逐步升高对VCR的处置没有显著影响，因此，所有恶性淋巴瘤患者和异基因造血干细胞移植患者无需担心HL - VCR相互作用。然而，HL是否会增强涉及VCR的其他药物 - 药物或药物 - 疾病相互作用，值得进一步研究和监测，以确保治疗的安全性和有效性。
