Giri S N
Exp Mol Pathol. 1986 Oct;45(2):207-20. doi: 10.1016/0014-4800(86)90060-2.
Pharmacokinetics, subcellular distribution (SCD), and covalent binding of a single dose of 1 microCi of [S-methyl-3H]bleomycin ([3H]-BLM]) in combination with one unit of unlabeled bleomycin were studied in hamsters following intratracheal (IT) injection. The radioactivity decreased from the lung biexponentially with time. The apparent half-time of absorption for the alpha-phase was 1.1 and 17.9 hr for the beta-phase. The plasma disappearance curve of [3H]BLM fits to a two-compartmental model with the apparent half-life removal for the alpha-phase being 1.6 hr and for the beta-phase 116.9 hr. The radioactivity was detected in all studied tissues. The radioactivity from spleen, testicle, liver, fat, RBC, brain, adrenal, and kidney manifested only the alpha-phase of the disappearance curve, while the beta-phase was complicated by redistribution processes. Of the eight tissues, the spleen had the shortest (2.0 hr) and kidney the longest (12.1 hr), and the remaining tissues had half-lives which ranged from 4 to 10 hr. The SCD study revealed that 85 to 95% of the total radioactivity in the lung and liver homogenate was associated with the soluble fraction (SF) at 30 min after treatment, thereafter, the radioactivity from both tissues gradually decreased to 60% of the total at 24 hr. The SF of the lung homogenate had the highest specific radioactivity (SRA) of any of the fractions during the period between 0.5 and 6 hr. The SRA, however, decreased biexponentially and attained a value similar to that of the mitochondrial and microsomal fractions at 12 and 24 hr after treatment. In the case of liver, the SF had the highest, the nuclear the lowest, and mitochondrial and microsomal fractions the same level of SRA at 30 min. Thereafter, the SRA of all fractions were increased with time. A significant amount of radioactivity from [3H]BLM was covalently bound to lung, liver, and plasma proteins. The SF of the lung contained an increasing amount of radioactivity covalently bound after 1.5 hr of [3H]BLM injection and nearly all radioactivity measured in the plasma was covalently bound. It was concluded from the findings of this study that the presence of a major portion of [3H]BLM in the SF of the lung and its covalent linkage with the proteins of this fraction might initiate the complex sequence of events at the metabolic level necessary for the pneumotoxicity.
在仓鼠经气管内（IT）注射单剂量1微居里的[S-甲基-³H]博来霉素（[³H]-BLM）并联合一单位未标记博来霉素后，研究了其药代动力学、亚细胞分布（SCD）及共价结合情况。放射性在肺内随时间呈双指数下降。α相的表观吸收半衰期为1.1小时，β相为17.9小时。[³H]BLM的血浆消除曲线符合二室模型，α相的表观消除半衰期为1.6小时，β相为116.9小时。在所有研究的组织中均检测到放射性。来自脾脏、睾丸、肝脏、脂肪、红细胞、脑、肾上腺和肾脏的放射性仅表现出消失曲线的α相，而β相则因再分布过程而变得复杂。在这八个组织中，脾脏的半衰期最短（2.0小时），肾脏最长（12.1小时），其余组织的半衰期在4至10小时之间。SCD研究表明，治疗后30分钟时，肺和肝匀浆中总放射性的85%至95%与可溶性部分（SF）相关，此后，两个组织中的放射性在24小时时逐渐降至总放射性的60%。在0.5至6小时期间，肺匀浆的SF具有所有组分中最高的比放射性（SRA）。然而，SRA呈双指数下降，在治疗后12小时和24小时达到与线粒体和微粒体组分相似的值。在肝脏中，治疗后30分钟时，SF的SRA最高，细胞核的最低，线粒体和微粒体组分的SRA相同。此后，所有组分的SRA均随时间增加。[³H]BLM的大量放射性与肺、肝和血浆蛋白共价结合。在注射[³H]BLM 1.5小时后，肺的SF中与共价结合的放射性量增加，血浆中测得的几乎所有放射性均为共价结合。从本研究结果得出结论，肺SF中[³H]BLM的主要部分及其与该组分蛋白质的共价连接可能在代谢水平引发肺毒性所需的一系列复杂事件。
