Burchiel S W, Oette D, Day P W, Stoll R E
University of New Mexico, College of Pharmacy, Albuquerque 87131.
Int J Immunopharmacol. 1994 Feb;16(2):75-90. doi: 10.1016/0192-0561(94)90063-9.
The purpose of these studies was to examine the biodistribution and pharmacokinetics of radiolabeled human CHO cell-derived rHuGM-CSF in normal Rhesus monkeys (Macaca mulatta) following intravenous (i.v.) and subcutaneous (s.c.) injection. A dual radioisotope tracer technique was utilized to monitor the behavior of rHuGM-CSF in vivo. Recombinant HuGM-CSF was radiolabeled with I-123 (a 13.2 h half-life, 140 KeV pure gamma emitting radionuclide detected using gamma scintigraphic imaging) using a mild chloramine T reaction. A separate preparation of rHuGM-CSF radiolabeled with S-35 methionine by bioincorporation in tissue culture was mixed with the I-123-labeled protein, permitting comparison of data obtained from the two radiolabels. Two dose levels of rHuGM-CSF were used for i.v. bolus (15 and 300 micrograms/kg) and s.c. (10 and 100 micrograms/kg) studies. The results of these studies demonstrated that the co-administered I-123 rHuGM-CSF and S-35 rHuGM-CSF followed similar blood elimination kinetics after i.v. or s.c. injection. Following i.v. bolus injection, rHuGM-CSF was found to rapidly distribute to all central body cavity high blood flow organs, followed by rapid uptake in the kidneys and elimination in the urine. There were no differences in the pharmacokinetic values obtained for I-123- and S-35-labeled rHuGM-CSF nor for the two dose levels examined. Following, s.c. injection, I-123- and S-35-labeled rHuGM-CSF were found to reach maximal plasma levels after approximately 16 h. The primary route of elimination was the urine. Monkeys previously exposed to rHuGM-CSF were found to have circulating antibodies to rHuGM-CSF. Studies in these animals revealed a significantly altered distribution and clearance of radiolabeled rHuGM-CSF, with the majority of the injected activity being cleared by the liver.
这些研究的目的是检查静脉注射（i.v.）和皮下注射（s.c.）后，放射性标记的人CHO细胞衍生的重组人粒细胞巨噬细胞集落刺激因子（rHuGM-CSF）在正常恒河猴（猕猴）体内的生物分布和药代动力学。采用双放射性同位素示踪技术监测rHuGM-CSF在体内的行为。重组人粒细胞巨噬细胞集落刺激因子用I-123（半衰期13.2小时，140千电子伏特纯γ发射放射性核素，使用γ闪烁成像检测）通过温和的氯胺T反应进行放射性标记。通过在组织培养中生物掺入S-35甲硫氨酸对rHuGM-CSF进行单独制备，并与I-123标记的蛋白质混合，从而能够比较从两种放射性标记获得的数据。两种剂量水平的rHuGM-CSF用于静脉推注（15和300微克/千克）和皮下注射（10和100微克/千克）研究。这些研究结果表明，静脉注射或皮下注射后，共同给药的I-123 rHuGM-CSF和S-35 rHuGM-CSF具有相似的血液消除动力学。静脉推注后，发现rHuGM-CSF迅速分布到所有体腔高血流器官，随后在肾脏中迅速摄取并经尿液排出。I-123标记和S-35标记的rHuGM-CSF以及所检测的两种剂量水平获得的药代动力学值没有差异。皮下注射后，发现I-123标记和S-35标记的rHuGM-CSF在约16小时后达到最大血浆水平。主要消除途径是尿液。发现先前接触过rHuGM-CSF的猴子体内有抗rHuGM-CSF的循环抗体。对这些动物的研究显示，放射性标记的rHuGM-CSF的分布和清除有显著改变，大部分注入的活性由肝脏清除。
