School of Pharmacy, Fudan University, Shanghai 201203, China.
School of Pharmacy, Fudan University, Shanghai 201203, China.
J Pharm Biomed Anal. 2018 Sep 10;159:217-223. doi: 10.1016/j.jpba.2018.06.057. Epub 2018 Jun 30.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. The discovery of new anticancer compounds is of great significance. GG-8-6, cyclo-(Val-Leu-Pro-Ile-Leu-Leu-Leu-Val-Leu), a new synthetic cyclic peptide, might be a potential candidate for developing new anti-HCC drugs. GG-8-6 shares no structural homology to current anti-HCC drugs. Therefore, it was necessary to develop a quantitative method for the determination of GG-8-6 in vivo. Herein, a simple, specific and sensitive liquid chromatographic method with tandem mass spectrometric detection (LC-MS/MS) was developed and validated for the analysis of GG-8-6 in rat plasma. GG-8-6 and the internal standard (IS), A6, cyclo-(Val-Leu-Pro-Ala-Leu-Leu-Leu-Val-Leu), were extracted from rat plasma by ethyl acetate. Chromatographic separation was performed on an Agilent Eclipse XDB-C18 column (4.6 × 150 mm, 5 μm) with a mobile phase consisting of acetonitrile-water containing 0.1% formic acid (90:10, v/v) with isocratic elution at a flow rate of 0.5 mL/min for 8.0 min. Multiple reaction monitoring (MRM) mode was performed with ion pairs of m/z: 974.8 → 861.8 for GG-8-6 and 932.7 → 819.8 for A6. The selectivity, matrix effects, recovery, intra- and inter-day precision and accuracy were validated with acceptable results in accordance with the US Food and Drug Administration guidelines. The calibration curve was linear (r > 0.99) over a concentration range of 1-1000 ng/mL with a lower limit of quantification (LLOQ) of 1 ng/mL. The method was successfully applied to the pharmacokinetic study of GG-8-6 in rats.
肝细胞癌（HCC）是全球癌症相关死亡的第二大主要原因。发现新的抗癌化合物具有重要意义。GG-8-6，环（缬氨酸-亮氨酸-脯氨酸-异亮氨酸-亮氨酸-亮氨酸-缬氨酸），一种新的合成环状肽，可能是开发新型抗 HCC 药物的潜在候选药物。GG-8-6 与当前的抗 HCC 药物没有结构同源性。因此，有必要开发一种用于体内测定 GG-8-6 的定量方法。本文建立并验证了一种用于大鼠血浆中 GG-8-6 分析的简单、特异和灵敏的液相色谱-串联质谱（LC-MS/MS）检测方法。GG-8-6 和内标（IS）A6，环（缬氨酸-亮氨酸-脯氨酸-丙氨酸-亮氨酸-亮氨酸-亮氨酸-缬氨酸），通过乙酸乙酯从大鼠血浆中提取。色谱分离在 Agilent Eclipse XDB-C18 柱（4.6×150mm，5μm）上进行，流动相由乙腈-水（含 0.1%甲酸，90:10，v/v）组成，采用等度洗脱，流速为 0.5mL/min，洗脱时间为 8.0min。采用多反应监测（MRM）模式，离子对为 m/z：974.8→861.8 用于 GG-8-6，932.7→819.8 用于 A6。根据美国食品和药物管理局的指南，该方法具有可接受的选择性、基质效应、回收率、日内和日间精密度和准确度。校准曲线在 1-1000ng/mL 浓度范围内呈线性（r＞0.99），定量下限（LLOQ）为 1ng/mL。该方法成功应用于大鼠 GG-8-6 的药代动力学研究。
