依那西普经静脉内和皮下给药后在大鼠体内的淋巴分布。

Lymphatic Distribution of Etanercept Following Intravenous and Subcutaneous Delivery to Rats.

机构信息

Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA.

Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA.

出版信息

Pharm Res. 2020 Jul 27;37(8):155. doi: 10.1007/s11095-020-02860-6.

DOI:10.1007/s11095-020-02860-6

PMID:32720159

Abstract

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.

摘要

目的

本研究旨在探讨淋巴系统在etanercept（一种融合蛋白）药代动力学中的作用。

方法

给胸部淋巴管插管和假手术对照大鼠静脉（IV）和皮下（SC）注射 1mg/kg 的 etanercept。在 6 天内采集血液和淋巴样本。

结果

对照组 SC 生物利用度为 65.2%。在淋巴管插管大鼠中，IV 给药后，淋巴中 etanercept 的浓度始终低于血清；SC 注射后，淋巴中的浓度明显高于血清。吸收主要通过淋巴途径（82.7%），仅有 17.3%通过直接进入中央隔室（血液途径）。与 IV 组相比，淋巴插管使血清 AUC 降低了 28%，与 SC 组相比，降低了 91%。建立了一个结合双吸收途径和系统内可利用蛋白药物再分布的机制药代动力学模型。该模型成功地同时捕获了所有组的血清和淋巴数据，并且所有参数都具有足够的精度进行估计。