Kuwabara T, Ishikawa Y, Kobayashi H, Kobayashi S, Sugiyama Y
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Pharm Res. 1995 Oct;12(10):1466-9. doi: 10.1023/a:1016227202781.
To clarify the role of the kidney in the elimination of a recombinant human granulocyte colony-stimulating factor, nartograstim, we have investigated its pharmacokinetics in rats with renal failure.
The steady-state clearance (CLss) were determined by the intravenous infusion for 4 hr to unilateral renally-ligated and cisplatin-treated rats, whose renal functions were about 50 and 10% of controls, respectively.
CLss of nartograstim (27 ml/hr/kg) in the renally-ligated rats at a high infusion rate was significantly lower (25%) than in control rats (p < 0.05). CLss in these rats, at a low infusion rate was 95 ml/hr/kg, 14% lower than in control rats. The saturable CLss in these rats, 68 ml/hr/kg, was not significantly different from control rats (75 ml/hr/kg, p > 0.05). Also, CLss in cisplatin-treated rats with extensive renal failure, at a high infusion rate, decreased to 57% of controls. Furthermore, the total body clearances (CLtot) of nartograstim after bolus intravenous administration to renally-ligated and cisplatin-treated rats were reduced to 33-49% of controls.
These results suggest that the kidney may be responsible for 40-50% of the nonsaturable clearance of nartograstim. Thus, the kidney should make a major contribution to the elimination of nartograstim when rats are given a high dose of nartograstim, which saturates the receptor-mediated clearance.
为阐明肾脏在重组人粒细胞集落刺激因子纳洛司亭消除过程中的作用，我们研究了其在肾衰竭大鼠体内的药代动力学。
通过对单侧肾结扎和顺铂处理的大鼠进行4小时静脉输注来测定稳态清除率（CLss），这些大鼠的肾功能分别约为对照组的50%和10%。
在高输注速率下，肾结扎大鼠中纳洛司亭的CLss（27 ml/hr/kg）显著低于对照大鼠（25%，p < 0.05）。在低输注速率下，这些大鼠的CLss为95 ml/hr/kg，比对照大鼠低14%。这些大鼠中可饱和的CLss为68 ml/hr/kg，与对照大鼠（75 ml/hr/kg，p > 0.05）无显著差异。此外，在高输注速率下，患有严重肾衰竭的顺铂处理大鼠的CLss降至对照组的57%。此外，对肾结扎和顺铂处理大鼠进行静脉推注后，纳洛司亭的总体清除率（CLtot）降至对照组的33 - 49%。
这些结果表明，肾脏可能负责纳洛司亭40 - 50%的非饱和清除。因此，当给大鼠高剂量纳洛司亭使其受体介导的清除饱和时，肾脏应在纳洛司亭的消除中起主要作用。
