Masuda H, Takakura Y, Hashida M
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Biochim Biophys Acta. 1999 Feb 2;1426(3):420-8. doi: 10.1016/s0304-4165(98)00163-9.
The pharmacokinetics and disposition characteristics of recombinant decorin after intravenous administration were investigated in mice. Following bolus injection of 111In-labeled decorin at doses of 0.02 and 0.1 mg/kg, radioactivity rapidly disappeared from the circulation and approximately 70% of the dose accumulated in liver within 10 min. 111In-labeled decorin was preferentially localized in hepatic nonparenchymal cells. At a higher dose of 1 mg/kg, clearance from the circulation and hepatic uptake of [111In]decorin were slower than at lower doses. Both the accumulation in other tissues and urinary excretion of [111In]decorin were 5% or less. Pharmacokinetic analysis demonstrated that hepatic uptake clearance was large and accounted almost completely for total body clearance; in addition the clearance values decreased as the dose increased, suggesting that the hepatic uptake of decorin is mediated by a specific mechanism which becomes saturated at higher doses. In competitive inhibition experiments, hepatic uptake of 111In-labeled decorin was partially inhibited (about 20-30%) by several sulfated glycans such as glycosaminoglycans and dextran sulfate and by mannosylated bovine serum albumin (BSA), mannan and mannose to a lesser extent (about 10%). On the other hand, polyinosinic acid, polycytidylic acid and succinylated BSA were ineffective, suggesting that the scavenger receptor for polyanions in the liver is not involved in the hepatic uptake of decorin. A basic protein, protamine, and a ligand of the apoE receptor, lactoferrin, also had no effect. Taken together, the present results have demonstrated that recombinant decorin is rapidly eliminated from the blood circulation through extensive uptake by the liver, primarily by the nonparenchymal cells, following systemic administration. The sugar structure and mannose residue in decorin have also been suggested to play an important role in the hepatic uptake of decorin. These findings provide useful information for the development of decorin as a therapeutic agent.
在小鼠中研究了静脉注射重组核心蛋白聚糖后的药代动力学和处置特征。以0.02和0.1mg/kg的剂量推注111In标记的核心蛋白聚糖后，放射性迅速从循环中消失，约70%的剂量在10分钟内积聚在肝脏中。111In标记的核心蛋白聚糖优先定位于肝非实质细胞。在1mg/kg的较高剂量下，[111In]核心蛋白聚糖从循环中的清除和肝脏摄取比低剂量时慢。[111In]核心蛋白聚糖在其他组织中的积聚和尿排泄均为5%或更低。药代动力学分析表明，肝脏摄取清除率很大，几乎完全占全身清除率；此外，清除率值随剂量增加而降低，表明核心蛋白聚糖的肝脏摄取是由一种特定机制介导的，该机制在较高剂量时会饱和。在竞争性抑制实验中，几种硫酸化聚糖如糖胺聚糖和硫酸葡聚糖以及甘露糖基化牛血清白蛋白（BSA）、甘露聚糖和甘露糖对111In标记的核心蛋白聚糖的肝脏摄取有部分抑制作用（约20-30%），程度较小的是甘露糖（约10%）。另一方面，聚肌苷酸、聚胞苷酸和琥珀酰化BSA无效，表明肝脏中多阴离子的清道夫受体不参与核心蛋白聚糖的肝脏摄取。一种碱性蛋白鱼精蛋白和载脂蛋白E受体的配体乳铁蛋白也没有作用。综上所述，目前的结果表明，重组核心蛋白聚糖在全身给药后通过肝脏（主要是非实质细胞）的广泛摄取而迅速从血液循环中消除。核心蛋白聚糖中的糖结构和甘露糖残基也被认为在核心蛋白聚糖的肝脏摄取中起重要作用。这些发现为核心蛋白聚糖作为治疗剂的开发提供了有用信息。
