Purpose

The purpose of this work was to investigate the role of the lymphatic system in the pharmacokinetics of etanercept, a fusion protein.

Methods

Etanercept 1 mg/kg was administered intravenously (IV) and subcutaneously (SC) to thoracic lymph duct-cannulated and sham-operated control rats. Blood and lymph samples were obtained for up to 6 days.

Results

Model-based SC bioavailability of etanercept was 65.2% in the control group. In lymph-cannulated rats, etanercept concentration in the lymph was consistently lower than in serum following IV dosing; and the concentration in the lymph was significantly higher than in serum after SC injection. The absorption occurred predominantly through the lymphatic pathway (82.7%), and only 17.3% by direct uptake into the central compartment (blood pathway). Lymphatic cannulation reduced the area under the serum concentration-time curve by 28% in IV group and by 91% in SC group. A mechanistic pharmacokinetic model that combined dual absorption pathways with redistribution of the systemically available protein drug into lymph was developed. The model successfully captured serum and lymph data in all groups simultaneously, and all parameters were estimated with sufficient precision.

Conclusions

Lymphatic system was shown to play an essential role in systemic disposition and SC absorption of etanercept.

中文翻译：

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静脉内和皮下递送给大鼠后，依那西普的淋巴分布。

目的

这项工作的目的是研究淋巴系统在融合蛋白依那西普的药代动力学中的作用。

方法

将Etanercept 1 mg / kg静脉内（IV）和皮下（SC）给予胸腔淋巴管插管和假手术的对照大鼠。采集血液和淋巴液样本长达6天。

结果

对照组依那西普基于模型的SC生物利用度为65.2％。静脉给药后，在淋巴管插管的大鼠中，淋巴中的依那西普浓度始终低于血清。注射SC后，淋巴浓度明显高于血清。吸收主要通过淋巴途径发生（82.7％），仅通过直接吸收进入中央腔室（血液途径）而发生17.3％。静脉插管使IV组的血清浓度-时间曲线下面积减少了28％，SC组减少了91％。建立了将双重吸收途径与全身可利用的蛋白药物重新分配到淋巴液中的机制的药代动力学模型。该模型可以同时成功捕获所有组的血清和淋巴数据，

结论

结果表明，淋巴系统在依那西普的全身性处置和SC吸收中起着至关重要的作用。