Sengupta S, Tyagi P, Velpandian T, Gupta Y K, Gupta S K
Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110029, India.
Pharmacol Res. 2000 Nov;42(5):459-64. doi: 10.1006/phrs.2000.0714.
Etoposide is an antineoplastic agent which acts by forming a ternary complex with topoisomerase II and DNA, causing DNA breaks and cell death. In recent studies we have demonstrated that encapsulation in liposomes increases the antitumour efficacy and reduces the adverse effects associated with etoposide. The present study was thus conducted to evaluate whether encapsulation in cationic liposomes altered the pharmacokinetics of etoposide and to study the effect of cholesterol incorporation on the stability of the liposomes. Etoposide-encapsulated unilammellar liposomes were synthesized by thin film hydration followed by extrusion. The drug was administered to Swiss albino mice at a dose of 10 mg kg(-1). The concentration of the drug in plasma was analysed at different time points till 360 min after injection, using a h.p.l.c. method. The terbium chloride-dipicolinic acid interaction method was applied to study the stability of the formulation in mouse serum and also following storage at 0( composite function)C over a period of time. The effect of the free and liposomal drug on myelosuppression was evaluated at 10 mg m(-2)and 40 mg m(-2)dose levels by quantifying blood cell counts on day 15 and day 21 following a 5 day course of therapy. Encapsulation in cationic liposomes increased the area under the concentration vs time curve to 42.98 microghml(-1)from 24.18 microghml(-1)in the case of the free drug. Half-life (beta) was 58. 62 and 186 min in the case of free and liposomal etoposide, respectively. In the stability studies, incorporation of cholesterol progressively stabilized the formulation in serum. The use of sucrose at increasing concentrations as a cryoprotectant also increased the shelf stability of the formulation at 0( composite function)C. Toxicity studies using a dose of pure drug revealed that though myelosuppression was evident in both liposomal- and free drug-treated groups on day 15 it was reversed by day 21 following initiation of therapy. The present findings suggest that liposomes could serve as an alternative mode of delivery for etoposide.
依托泊苷是一种抗肿瘤药物，其作用机制是与拓扑异构酶II和DNA形成三元复合物，导致DNA断裂和细胞死亡。在最近的研究中，我们已经证明，脂质体包封可提高抗肿瘤疗效，并减少与依托泊苷相关的不良反应。因此，本研究旨在评估阳离子脂质体包封是否会改变依托泊苷的药代动力学，并研究胆固醇掺入对脂质体稳定性的影响。通过薄膜水化然后挤压的方法合成了包封有依托泊苷的单层脂质体。以10 mg kg(-1)的剂量将药物给予瑞士白化小鼠。使用高效液相色谱法在注射后直至360分钟的不同时间点分析血浆中的药物浓度。采用氯化铽-吡啶二甲酸相互作用法研究该制剂在小鼠血清中的稳定性以及在0（复合函数）℃下储存一段时间后的稳定性。通过在为期5天的治疗后的第15天和第21天对血细胞计数进行定量，评估游离药物和脂质体药物在10 mg m(-2)和40 mg m(-2)剂量水平下对骨髓抑制的影响。阳离子脂质体包封使浓度-时间曲线下面积从游离药物的24.18 microghml(-1)增加到42.98 microghml(-1)。游离依托泊苷和脂质体依托泊苷的半衰期（β）分别为58.62分钟和186分钟。在稳定性研究中，胆固醇的掺入逐渐使制剂在血清中稳定。使用浓度不断增加的蔗糖作为冷冻保护剂也提高了制剂在0（复合函数）℃下的储存稳定性。使用纯药物剂量进行的毒性研究表明，虽然在治疗开始后的第15天，脂质体药物治疗组和游离药物治疗组均出现明显的骨髓抑制，但在第21天这种抑制作用得到了逆转。目前的研究结果表明，脂质体可以作为依托泊苷的一种替代给药方式。
