McLennan Danielle N, Porter Christopher J H, Edwards Glenn A, Brumm Maria, Martin Steven W, Charman Susan A
Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, 381 Royal Parade Parkville, Parkville, Victoria 3052, Australia.
Pharm Res. 2003 Aug;20(8):1156-62. doi: 10.1023/a:1025036611949.
The purpose of this work was to develop a pharmacokinetic model to describe the contribution of the lymphatics to the absorption and bioavailability of r-metHu-Leptin administered by subcutaneous (SC) injection to sheep.
r-metHu-Leptin was administered either by bolus intravenous injection (0.1 mg/kg) into the jugular vein or by SC injection (0.15 mg/kg) into the interdigital space of the hind leg. The SC groups included a non-cannulated control group and a lymph-cannulated group, in which peripheral lymph was continuously collected from a cannula in the efferent popliteal lymph duct. Serum and lymph concentrations were determined by enzyme-linked immunosorbent assay and profiles were modeled using compartmental pharmacokinetic methods. The fraction of the dose reaching the systemic circulation (Fsys) and the proportions of the absorbed dose taken up via the blood (Fblood) and lymph (Flymph) were determined.
Serum and lymph concentration vs. time profiles were well described by a two compartment model with parallel first order absorption into blood and lymph. Fsys for the SC control group was 60.4 +/- 8.4%. In the lymph-cannulated group, 21.7 +/- 6.4% of the dose was recovered in serum and 34.4 +/- 9.7% was recovered in peripheral lymph giving a total fraction absorbed (Fabs) of 56.0 +/- 10.3%. Fsys for the SC control group was not significantly different to Fabs in the lymph-cannulated group.
This study has shown that the lymph represents the predominant pathway for absorption of r-metHu-Leptin after SC administration.
本研究旨在建立一个药代动力学模型，以描述淋巴管对皮下（SC）注射给绵羊的重组人甲硫氨酸化瘦素（r-metHu-Leptin）吸收及生物利用度的贡献。
r-metHu-Leptin通过颈静脉大剂量静脉注射（0.1mg/kg）或后肢趾间间隙SC注射（0.15mg/kg）给药。SC组包括非插管对照组和淋巴管插管组，后者通过腘淋巴结输出淋巴管中的插管持续收集外周淋巴液。采用酶联免疫吸附测定法测定血清和淋巴液浓度，并使用房室药代动力学方法对药时曲线进行建模。确定到达体循环的剂量分数（Fsys）以及通过血液（Fblood）和淋巴（Flymph）吸收的剂量比例。
血清和淋巴液浓度-时间曲线可用二房室模型很好地描述，药物以一级动力学平行吸收进入血液和淋巴。SC对照组的Fsys为60.4±8.4%。在淋巴管插管组中，21.7±6.4%的剂量在血清中回收，34.4±9.7%的剂量在外周淋巴液中回收，总吸收分数（Fabs）为56.0±10.3%。SC对照组的Fsys与淋巴管插管组的Fabs无显著差异。
本研究表明，SC给药后，淋巴是r-metHu-Leptin吸收的主要途径。
