Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium.
The Second Affiliated Hospital, Xi'an Medical University, Xi'an, Shaanxi, China.
Pharm Res. 2023 Jul;40(7):1723-1734. doi: 10.1007/s11095-023-03536-7. Epub 2023 May 31.
Colistin is an antibiotic which is increasingly used as a last-resort therapy in critically-ill patients with multidrug resistant Gram-negative infections. The purpose of this study was to evaluate the mechanisms underlying colistin's pharmacokinetic (PK) behavior and to characterize its hepatic metabolism.
In vitro incubations were performed using colistin sulfate with rat liver microsomes (RLM) and with rat and human hepatocytes (RH and HH) in suspension. The uptake of colistin in RH/HH and thefraction of unbound colistin in HH (f) was determined. In vitro to in vivo extrapolation (IVIVE) was employed to predict the hepatic clearance (CL) of colistin.
Slow metabolism was detected in RH/HH, with intrinsic clearance (CL) values of 9.34± 0.50 and 3.25 ± 0.27 mL/min/kg, respectively. Assuming the well-stirred model for hepatic drug elimination, the predicted rat CL was 3.64± 0.22 mL/min/kg which could explain almost 70% of the reported non-renal in vivo clearance. The predicted human CL was 91.5 ± 8.83 mL/min, which was within two-fold of the reported plasma clearance in healthy volunteers. When colistin was incubated together with the multidrug resistance-associated protein (MRP/Mrp) inhibitor benzbromarone, the intracellular accumulation of colistin in RH/HH increased significantly.
These findings indicate the major role of hepatic metabolism in the non-renal clearance of colistin, while MRP/Mrp-mediated efflux is involved in the hepatic disposition of colistin. Our data provide detailed quantitative insights into the hereto unknown mechanisms responsible for non-renal elimination of colistin.
多黏菌素是一种抗生素，在患有多重耐药革兰氏阴性感染的重症患者中，作为最后手段的治疗药物，其应用日益增多。本研究的目的是评估多黏菌素药代动力学（PK）行为的机制，并对其肝代谢进行特征描述。
使用硫酸多黏菌素与大鼠肝微粒体（RLM）以及悬浮的大鼠和人肝细胞（RH 和 HH）进行体外孵育。测定 RH/HH 中多黏菌素的摄取和 HH 中未结合多黏菌素的分数（f）。采用体外向体内外推算法（IVIVE）预测多黏菌素的肝清除率（CL）。
在 RH/HH 中检测到缓慢的代谢，其内在清除率（CL）值分别为 9.34±0.50 和 3.25±0.27 mL/min/kg。假设肝药物消除的完全搅拌模型，预测大鼠 CL 为 3.64±0.22 mL/min/kg，这几乎可以解释报道的非肾体内清除率的 70%。预测的人体 CL 为 91.5±8.83 mL/min，这与健康志愿者中报道的血浆清除率相差两倍。当多黏菌素与多药耐药相关蛋白（MRP/Mrp）抑制剂苯溴马隆一起孵育时，RH/HH 中多黏菌素的细胞内积累显著增加。
这些发现表明肝代谢在多黏菌素的非肾清除中起主要作用，而 MRP/Mrp 介导的外排参与多黏菌素的肝处置。我们的数据提供了对迄今为止未知的多黏菌素非肾消除机制的详细定量见解。
