Yoo S D, Jun H, Shin B S, Lee H S, Park M O, Deluca P P, Lee K C
College of Pharmacy, Sungkyunkwan University, Suwon, Kyonggi-do, Korea.
Chem Pharm Bull (Tokyo). 2000 Dec;48(12):1921-4. doi: 10.1248/cpb.48.1921.
This study first reports the pharmacokinetic disposition of polyethylene glycol (PEG)-modified salmon calcitonin (sCT) based on the number of attached PEG molecules. PEG-modified sCT was prepared by covalent linkage with succinimidyl carbonate monomethoxy polyethylene glycol. Mono- and di-PEG-sCTs were separated by size exclusion and reverse phase HPLC, and radioiodinated by the chloramine-T method with Na125I. 125I-mono-PEG sCT, 125I-di-PEG-sCT and unmodified 125I-sCT were administered to rats by i.v. injection. Serial blood samples, urine and various tissue samples were taken for the determination of radioactivity. Di-PEG-sCT exhibited significantly reduced systemic clearance (2.3 vs. 11.1 ml/min/kg) and steady-state volume of distribution (229.9 vs. 603.1 ml/kg), while mono-PEG-sCT showed a prolonged elimination half-life (189.1 min vs. 59.8 min) compared with unmodified sCT. The extent of urinary excretion of the PEG-modified sCTs was higher than for the unmodified sCT, but all these chemicals were excreted in urine in small quantities (< or = 0.6%). There was a tendency toward reduced accumulation of PEGylated sCTs in tissues, with its reduction being inversely proportional to the molecular size. Accumulation of the total radioactivity of the unmodified and PEG-modified sCTs was highest in the liver, followed by kidneys, lungs, spleen, heart and thyroid. When expressed per tissue gram weight, however, the highest radioactivity was found in the kidneys. PEGylated sCTs may have greater therapeutic potential via reduced systemic clearance and prolonged elimination half-life over unmodified sCT.
本研究首次报道了基于连接的聚乙二醇（PEG）分子数量的聚乙二醇（PEG）修饰鲑鱼降钙素（sCT）的药代动力学特征。PEG修饰的sCT通过与琥珀酰亚胺碳酸酯单甲氧基聚乙二醇共价连接制备。单PEG-sCT和双PEG-sCT通过尺寸排阻和反相高效液相色谱分离，并用氯胺-T法用Na125I进行放射性碘化。125I-单PEG sCT、125I-双PEG-sCT和未修饰的125I-sCT通过静脉注射给予大鼠。采集系列血样、尿液和各种组织样本以测定放射性。与未修饰的sCT相比，双PEG-sCT的全身清除率显著降低（2.3对11.1 ml/min/kg），稳态分布容积降低（229.9对603.1 ml/kg），而单PEG-sCT的消除半衰期延长（189.1分钟对59.8分钟）。PEG修饰的sCT的尿排泄程度高于未修饰的sCT，但所有这些化学物质在尿液中的排泄量都很少（≤0.6%）。PEG化sCT在组织中的蓄积有减少的趋势，其减少与分子大小成反比。未修饰和PEG修饰的sCT的总放射性在肝脏中蓄积最高，其次是肾脏、肺、脾脏、心脏和甲状腺。然而，以每克组织重量表示时，肾脏中的放射性最高。与未修饰的sCT相比，PEG化sCT通过降低全身清除率和延长消除半衰期可能具有更大的治疗潜力。
