Khalil Hadeel A, ElKhatib Mohammed A W, Belal Tarek S, El-Yazbi Ahmed F, Hamdy Dalia A
Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Alexandria University, 1 El Khartoum Square, P.O. Box 21521, Alexandria, 21521, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Drugs R D. 2017 Jun;17(2):287-296. doi: 10.1007/s40268-017-0178-8.
Co-administration of posaconazole (PSZ) and vincristine (VCR) in the treatment of patients with acute lymphoblastic leukemia increases the neurotoxicity of VCR. Our aim is to study the effect of increased lipoprotein levels on the pharmacokinetics of PSZ and VCR upon co-administration in rats.
Rats were assigned to three groups, normolipidemic (NL), intermediate hyperlipidemic (IHL), and extreme hyperlipidemic (HL) groups. All rats were administered PSZ orally followed by VCR intravenously 4 h later. For the pharmacokinetic study, serial plasma samples were collected over 96 h and for tissue distribution study; plasma, lung, and liver tissues were collected over 48 h post oral dosing.
Posaconazole showed higher plasma concentrations than VCR at all time points. Co-administration of VCR with PSZ reduced PSZ weight normalized oral clearance, increased PSZ area under the plasma concentration-time curve (AUC) from time zero to infinity, showed higher PSZ liver concentrations, and increased VCR volume of distribution of the central compartment. Upon increasing the lipoprotein levels, PSZ showed higher plasma availability and delayed tissue distribution, whereas VCR had shown a significant decrease in PSZ AUC, AUC, and AUC (NL = IHL > HL) and a significant increase in the volume of distribution (NL = IHL < HL). Vincristine has shown higher tissue uptake and concentrations.
Monitoring cholesterol and triglyceride levels in patients with acute lymphoblastic leukemia is advisable to decrease VCR neurological side effect incidences and delay the activity of both PSZ and VCR.
泊沙康唑（PSZ）与长春新碱（VCR）联合用于治疗急性淋巴细胞白血病患者时，会增加VCR的神经毒性。我们的目的是研究脂蛋白水平升高对大鼠联合使用PSZ和VCR时的药代动力学的影响。
将大鼠分为三组，即正常血脂（NL）组、中度高脂血症（IHL）组和极度高脂血症（HL）组。所有大鼠均口服PSZ，4小时后静脉注射VCR。为进行药代动力学研究，在96小时内采集系列血浆样本；为进行组织分布研究，在口服给药后48小时内采集血浆、肺和肝组织样本。
在所有时间点，泊沙康唑的血浆浓度均高于长春新碱。VCR与PSZ联合使用降低了PSZ的体重标准化口服清除率，增加了PSZ从零时到无穷大的血浆浓度 - 时间曲线下面积（AUC），显示出更高的PSZ肝脏浓度，并增加了VCR中央室的分布容积。随着脂蛋白水平的升高，PSZ显示出更高的血浆可用性和延迟的组织分布，而VCR则显示PSZ的AUC、AUC和AUC显著降低（NL = IHL > HL），分布容积显著增加（NL = IHL < HL）。长春新碱显示出更高的组织摄取和浓度。
建议监测急性淋巴细胞白血病患者的胆固醇和甘油三酯水平，以降低VCR神经副作用的发生率，并延迟PSZ和VCR的活性。
