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[摘要]
目的研究重组水蛭素iv给药在大鼠体内的药动学。方法采用125-标记的放射性同位素法(RA法)、三氯醋酸沉淀结合放射性检测法(TCA-RA法)研究重组水蛭素iv给药在大鼠体内的药动学。结果大鼠iv0.5、1.0和2.0mg/kg重组水蛭素,以RA法检测,该药的消除半衰期(t1/2ke)分别为162.8、147.5和172.8min,AUC分别为264.9、429.9和1112.9(μg·min)/mL;以TCA-RA法检测,该药的t1/2ke分别为100、101和107min,AUC分别为160.7、327.7和551.3(μg·min)/mL。两种方法所得结果均证明AUC与剂量呈正相关,相关系数均大于0.99。大鼠iv重组水蛭素1.0mg/kg后用RA法和TCA-RA法测定不同组织的药物质量浓度,在各时间点以肾脏含药量显著高于其他组织,肺、胃、脾、心、肝、性腺等组织次之,脑、脂肪最少。大鼠iv重组水蛭素1.0mg/kg后,用RA法测定不同时间段内尿、粪的放射性总量,在96h内70.16%放射性从尿中回收,1.35%从粪中回收到,24h内胆汁排泄量为3.46%。结论RA法和TCA-RA法测得重组水蛭素在大鼠体内的药动学结果不同,但整体趋势一致;重组水蛭素主要由尿排泄。
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[Abstract]
Objective To investigate the pharmacokinetics of recombinant hirudin (r-hirudin) after iv administration in rats. Methods Two Methods, total radioisotope assay with 125I-labeled (RA), the radioactivity assay after sample deposited with trichloroacetic acid (TCA-RA), were used to detect r-hirudin after iv administration in rats. Results Rats were given 0.5, 1.0, and 2.0 mg/kg r-hirudin by iv. The pharmacokinetic parameters determined by RA method were as follows: the elimination half-life t_ 1/2ke were 162.8, 147.5, and 172.8 min, AUC were 264.9, 429.9, and 1 112.9 (μg·min)/mL. The pharmacokinetic parameters determined by TCA-RA method were as follow: t_ 1/2ke were 100, 101, and 107 min, AUC were 160.7, 327.7, and 551.3 (μg·min)/mL. AUC were correlated with doses positively for the two Methods (r0.99). After iv 125I-labeled r-hirudin (1.0 mg/kg) administration, the rank order of accumulation of 125I-radiolabeled in the major organs was kidneylungstomachspleenheartlivergenitai glandbrain and fatty. The accumulation excretion ratios within 96 h were 70.16% in urine and only 1.35% in feces after iv administration in rats, while within 24 h was 3.46% in bile. Conclusion The Results of pharmacokinetics of novel r-hirudin in rats given by iv determined by RA are different from those determined by TCA-RA, but the trends indicated by the two Methods are the same; urine excretion is the major excretion pathway.
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[基金项目]
国家“863”项目资助(2003AA2Z347D)