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目的:建立格尔德霉素在 Beagle 犬血浆中的同相萃取(SPE)-HPLC 测定方法,并研究其在犬体内的药代动力学。方法:18只 Beagle 犬分为0.25,0.5,1.0 mg·kg~(-1)低、中、高3个剂量组,单次静脉注射格尔德霉素,于给药后不同时间点采集血样。以 N-苯基-1-萘胺作为内标,Oasis HLB 同相萃取柱优化提取富集,HPLC 法测定其浓度;用药代动力学计算程序3P97拟合药物浓度-时间曲线,求算药动学参数。结果:格尔德霉素在0.01-1.0μg·mL~(-1)线性范围内,低、中、高3种不同浓度质控样品(0.01,0.1,1.0μg·mL~(-1))日内 RSD 分别为5.6%,4.6%,1.9%(n=5);日间 RSD 分别为6.9%,3.2%,6.7%(n=5)。绝对回收率分别为85.0%±3.0%,91.1%±2.2%,94.0%±0.7%(n=5);低、中、高剂量组的 T_(1/2β)分别为89.2,116.6,101.6 min;AUC 分别为6.9,12.7,24.9 min·μg·mL~(-1);Vc 分别为858.0,964.4,981.3 mL·kg~(-1);CL 分别为35.9,39.4,40.1mL·min~(-1)·kg~(-1)。结论:固相萃取-HPLC 法测定格尔德霉素准确,快速,回收率高。格尔德霉素在 Beagle 犬体内药代动力学符合二室静脉注射模型。这对以后的临床应用指导具有十分重要的意义。
Objective: To establish a method for the determination of geldanamycin in Beagle dog’s plasma by phase-extraction (SPE) -HPLC and study its pharmacokinetics in dogs. Methods: 18 Beagle dogs were divided into three groups: low, medium and high dosage of 0.25, 0.5 and 1.0 mg · kg -1, single dose of geldanamycin, blood samples were collected at different time points . Using N-phenyl-1-naphthylamine as internal standard, the Oasis HLB in-phase extraction column was optimized for extraction and concentration, and its concentration was determined by HPLC. Pharmacokinetic calculation program 3P97 was used to fit the drug concentration-time curve to calculate the pharmacokinetics parameter. Results: In the linear range of 0.01-1.0 μg · mL -1, geldanamycin had low, medium and high quality control samples (0.01,0.1,1.0 μg · mL -1) The intra-day RSD was 5.6%, 4.6% and 1.9%, respectively (n = 5). The daytime RSD was 6.9%, 3.2% and 6.7% respectively (n = 5). The absolute recoveries were 85.0% ± 3.0%, 91.1% ± 2.2% and 94.0% ± 0.7% respectively (n = 5). The T 1 / 2β of low, medium and high dose groups were 89.2, 116.6 and 101.6 min ; AUC were 6.9,12.7,24.9 min · μg · mL -1, Vc were 858.0,964.4,981.3 mL · kg -1, CL were 35.9,39.4 and 40.1 mL · min -1 -1) · kg -1 (-1). Conclusion: Solid-phase extraction-HPLC method for determination of geldanamycin is accurate, rapid and high recovery rate. The geldanamycin pharmacokinetics in Beagle dogs fit the two-compartment intravenous model. This is of great significance for future clinical application guidance.