Oncology Clinical Pharmacology, Pfizer Inc., San Diego, California, USA.
Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.
Clin Pharmacol Ther. 2020 Jul;108(1):136-144. doi: 10.1002/cpt.1824. Epub 2020 Apr 1.
Significant in vitro and in vivo evidence supports the potential use of sertraline as an anticancer and antimicrobial agent. Yet, it is unknown whether effective sertraline concentrations are clinically achieved at therapeutic doses. The study objectives were to develop a physiologically-based pharmacokinetic (PBPK) model of sertraline and estimate the probability of achieving effective concentrations in various human tissues. A generic PBPK model consisting of perfusion-limited compartments representing the body organs linked together by blood flows and incorporated with clearance, tissue distribution, and absorption models was implemented in R using the mrgsolve package. Sertraline clearance and volume of distribution were first optimized from i.v. plasma concentration data then absorption and bioavailability were optimized from oral data. Predicted unbound sertraline concentrations at steady-state in human tissues did not reach concentrations determined in vitro, indicating therapeutic doses of sertraline are unlikely to produce concentrations required for anticancer and antimicrobial activities in humans.
大量的体外和体内证据支持舍曲林作为一种抗癌和抗菌药物的潜在用途。然而，目前尚不清楚在治疗剂量下，是否能在临床上达到有效的舍曲林浓度。本研究的目的是建立舍曲林的生理基于药代动力学（PBPK）模型，并估计在各种人体组织中达到有效浓度的概率。一个通用的 PBPK 模型由代表身体器官的灌注受限隔室组成，这些隔室通过血流连接在一起，并结合了清除率、组织分布和吸收模型，该模型在 R 中使用 mrgsolve 包实现。舍曲林的清除率和分布容积首先从静脉内血浆浓度数据进行优化，然后从口服数据优化吸收和生物利用度。在稳态下人组织中未达到预测的游离舍曲林浓度，这表明治疗剂量的舍曲林不太可能产生在人体中进行抗癌和抗菌活动所需的浓度。
