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目的:建立一种灵敏、稳定的新型靶向侯选化合物N-苄氧羰基-甘氨酰脯氨酸表阿霉素(Z-GP-EPI)体内分析方法,并考察大鼠单次给药血药浓度变化及求算药代动力学参数。方法:液-液萃取法进行样品处理。色谱条件:色谱柱为UltimateXB-C18(4.6 mm×250 mm,5μm);流动相为乙腈-0.1%TFA水(45∶55,v/v);流速为1 mL.min-1;荧光检测器,激发波长为495 nm,发射波长为590 nm。SD大鼠颈静脉注射给药(18 mg.kg-1),HPLC测定血药浓度经时变化,绘制平均血药浓度-时间曲线,统计矩模型估算药代动力学参数。结果:Z-GP-EPI在0.1～100μg.mL-1浓度范围内线性相关性良好(r=0.9993),回归方程为:Y=0.526X-0.014,定量下限为0.1μg.mL-1。低、中、高质控样品的萃取回收率、日间/日内精密度与准确度均符合化学药物非临床药代动力学技术指导原则。主要药代动力学参数如下:AUC0-∞为(10.165±2.863)μg.mL-1.h,MRT0-∞为(1.283±0.629)h,t1/2z为(2.208±1.475)h,Vz为(5.458±2.80)L.kg-1,CLz为(1.714±0.885)L.h-1.kg。结论:建立稳定、可靠的Z-GP-EPI体内分析方法,为后续开展系统性药代动力学研究奠定基础。
OBJECTIVE: To establish a sensitive and stable candidate target compound for N-carbobenzoxy-glycyl-proline epirubicin (Z-GP-EPI) in vivo and to study the effect of single administration Changes in plasma concentration and calculation of pharmacokinetic parameters. Methods: Liquid-liquid extraction was used for sample processing. Chromatographic conditions: the column was UltimateXB-C18 (4.6 mm × 250 mm, 5 μm); the mobile phase was acetonitrile-0.1% TFA water (45:55, v / v); the flow rate was 1 mL.min-1; Detector, the excitation wavelength is 495 nm and the emission wavelength is 590 nm. Sprague-Dawley rats were injected with jugular vein (18 mg.kg-1). The changes of plasma concentration were determined by HPLC. The mean plasma concentration-time curve was plotted. Pharmacokinetic parameters were estimated by statistical moment model. Results: The linearity of Z-GP-EPI was linear in the range of 0.1-100μg.mL-1 (r = 0.9993). The regression equation was Y = 0.526X-0.014 and the lower limit of quantification was 0.1μg.mL-1. Low, medium and high quality control samples extraction recovery, day / day precision and accuracy are in line with non-clinical pharmacokinetic technical guidelines. The main pharmacokinetic parameters were as follows: AUC0-∞ of (10.165 ± 2.863) μg.mL-1.h, MRT0-∞ of 1.283 ± 0.629 h, t1 / 2z of 2.208 ± 1.475 h, 5.458 ± 2.80) L.kg-1 and CLz was (1.714 ± 0.885) Lh -1.kg. Conclusion: The establishment of a stable and reliable in vivo analytical method of Z-GP-EPI lays the foundation for further systematic pharmacokinetic studies.