氚标记的Bcl-2反义核酸(F951)在小鼠体内的药代动力学实验研究

目的　研究一种新的氚标记的Bcl 2反义寡核苷酸 3H F95 1单次静脉注射后在小鼠体内的药代动力学过程。方法　用氚标记F95 1,用液闪仪检测放射性浓度 ,用 3P87软件判断房室模型 ,计算各种参数。用液闪仪检测3H F95 1在小鼠体内各器官中的分布浓度 ,检测给药后 72h内药物从小鼠尿和粪中排泄的量。结果　3H F95 1单次静脉注射后在小鼠体内的动力学过程符合二室模型 ,3种剂量时主要的参数血浆分布半衰期 (T1/ 2α)在 10～ 15min之间 ,消除半衰期 (T1/ 2 β)在 2～ 4 5h之间。3H F95 1在肾、肝、脾、骨髓中分布浓度高于其它器官 ,在心、肺、脑、肠、皮肤、脂肪、生殖腺中也有低水平的分布。3H F95 1主要经肾从尿中排泄 ,给药后 2 4h内的累积排泄量占给药量的 5 0 47%。3H F95 1从粪中排泄的量甚微。结论　3H F95 1在小鼠体内药代动力学过程的研究为其进一步的开发具有指导价值

Pharmacokinetic properties and biodistribution of [ 3H]-labeled F951 in mice following intravenous injection

AIM To investigate the pharmacokinetic properties and biodistribution of 3H labeled F951, a novel antisense phosphorothioate oligodeo xynucleotide to Bcl 2, in mice following intravenous single injection.METHODS Three groups of BALB/c mice were administered an intravenous(iv) bolus dose of 3H labeled F951(5, 10, 20 mg·kg -1 ), and blood were taken at specific times up to 48 hours. Radioactivity was measured in all samples. Data were analyzed using 3P87 software. Biodistribution of 3H labeled F951 in mice was examined with liquid scintillation counting. The excretion of 3H labeled F951 from urine and feces was also detected. RESULTS According to the data, a two compartment model was selected for the curve fitting. The distribution half lives( T 1/2α ) ranged from 10 to 15 minutes and the elimination half lives( T 1/2β ) ranged from 2 to 4 5 hours based on radioactivity levels. The maximum plasma concentration of F951 and the area under the plasma concentration time curve were associated with the dose administered. 3H labeled F951 distributed widely into tissues, but the relative affinity varied enormously, being higher for kidney, liver, spleen and bone marrow and lower for other tissues. Urinary excretion represented the major pathway of elimination, with 50 47% of the administered dose excreted in urine over 24 hours.CONCLUSION These findings indicate that F951 has potential therapeutic use as a drug in vivo.