Shenyang Pharmaceutical University, Department of Pharmaceutics , 103 Wenhua Road, Shenyang 110016 , China.
Expert Opin Drug Deliv. 2013 May;10(5):559-71. doi: 10.1517/17425247.2013.769954. Epub 2013 Feb 4.
This work aimed to evaluate pharmacokinetics, biodistribution, toxicity, and antitumor activities of a highly stable long-/medium-chain triglycerides (LCT/MCT)-based etoposide parenteral emulsion (EPE) in comparison to etoposide parenteral solution (EPS).
Using high-pressure homogenization method, EPE was prepared and sterilized at 121°C for 10 min by autoclaving. The biological samples were analyzed using the UPLC-ESI-MS/MS method.
Superior stability of EPE was verified with no significant changes in physicochemical properties in the accelerating and long-term stability tests. Similar pharmacokinetic behavior in beagle dogs was obtained and the AUC 0 - 12h values were 1196.73 ± 320.85 and 1505.56 ± 617.93 µg.h/L for EPE and EPS (p > 0.5), respectively. Likewise, no remarkable difference in biodistribution profiles in mice was found for both formulations. Safety assessment studies including hemolysis test, rabbit ear vein test and injection anaphylaxis were undertaken and the EPE was proven to be safe for intravenous administration. Specifically, after consecutive 12 weeks administration in rats, systematic and local toxicity induced by EPE were alleviated relative to that of EPS. Furthermore, significant and comparable antitumor activities to EPS were also demonstrated by EPE with tumor suppression rate (TSR) of 66.63, 55.94, and 60.16% against H460, Hep G2, and BCAP-37 human cancer cell lines in nude mice at the dose of 15 mg/kg, respectively.
These results suggest that this LCT/MCT-based lipid emulsion is a promising alternative intravenous carrier for etoposide with high stability, improved convenience, alleviated toxicity, and noncompromised antitumor efficacy.
本研究旨在评估一种基于长链/中链甘油三酯（LCT/MCT）的依托泊苷长/中链脂肪乳注射液（EPE）与依托泊苷注射液（EPS）相比的药代动力学、生物分布、毒性和抗肿瘤活性。
采用高压匀质法制备 EPE，并于 121℃高压蒸汽灭菌 10min。采用 UPLC-ESI-MS/MS 法分析生物样品。
加速和长期稳定性试验证明 EPE 具有优越的稳定性，理化性质无显著变化。在比格犬中获得了相似的药代动力学行为，EPE 和 EPS 的 AUC0-12h 值分别为 1196.73±320.85 和 1505.56±617.93μg·h/L（p＞0.5）。同样，两种制剂在小鼠体内的生物分布特征也无明显差异。进行了溶血试验、兔耳静脉试验和注射过敏试验的安全性评估，结果表明 EPE 静脉注射安全。具体而言，在大鼠连续给药 12 周后，EPE 引起的全身和局部毒性较 EPS 减轻。此外，EPE 也表现出与 EPS 相当的抗肿瘤活性，在 15mg/kg 剂量下对 H460、Hep G2 和 BCAP-37 人癌细胞系的肿瘤抑制率（TSR）分别为 66.63%、55.94%和 60.16%。
这些结果表明，这种基于 LCT/MCT 的脂肪乳剂是依托泊苷的一种有前途的静脉用替代载体，具有高稳定性、改善的便利性、减轻的毒性和不降低的抗肿瘤疗效。
