Department of Pharmacotherapy and Translational Research, University of Florida, College of Pharmacy, 1600 SW Archer Road, RM PG-23, Gainesville, FL 32610-0486, United States.
Toxicology. 2010 Apr 11;270(2-3):59-65. doi: 10.1016/j.tox.2010.01.009. Epub 2010 Jan 25.
A series of studies were designed and carried out in order to explore the potential for the major human hepatic hydrolase, carboxylesterase 1 (hCES1), to serve as a target of metabolic inhibition by a variety of medications. The risk of adverse drug-drug interaction(s) is present when metabolic inhibitors are combined with known or suspected substrates of a given enzyme. In the present report the abundantly expressed hepatic enzyme, hCES1, was examined as a potential target of metabolic inhibition by a number of routinely prescribed medications. hCES1 has been seldom assessed in this regard despite its role in the metabolism and detoxification of many compounds. The psychostimulant methylphenidate (MPH) was chosen as an hCES1 selective substrate. In vitro studies were performed using previously developed cell lines which overexpress hCES1 with both p-nitrophenyl acetate and d-MPH serving as known substrates. Aripiprazole, perphenazine, thioridazine, and fluoxetine were determined to be the potent hCES1 inhibitors. A complementary animal study followed in vitro screening studies to further evaluate the inhibitory effect of aripiprazole on CES1 activity in FVB mice. The results suggest that the concurrent administration of racemic (i.e. dl-) MPH with aripiprazole significantly increased the plasma concentrations of both total MPH as well as the less active l-isomer. The ratio of d-MPH and l-MPH plasma concentrations was significantly decreased in the mice treated with aripiprazole compared to the control animals, indicating an overall decrease of CES1 catalytic activity in aripiprazole treated animals. Additionally, a quantitative structure-activity relationship based analysis identified a number of structural similarities of CES1 inhibitors. In conclusion, drug-drug interactions with MPH are likely mediated via CES1 inhibition as a result of concomitant drug therapies. CES1 inhibition represents an overlooked and little studied source of variability in MPH disposition, tolerability, and response.
为了探索主要的人类肝水解酶羧酸酯酶 1（hCES1）是否有可能成为多种药物代谢抑制的靶点，设计并进行了一系列研究。当代谢抑制剂与已知或疑似特定酶的底物合用时，存在药物相互作用的风险。在本报告中，大量表达的肝酶 hCES1 被视为多种常规处方药物代谢抑制的潜在靶点。尽管 hCES1 在许多化合物的代谢和解毒中发挥作用，但在这方面很少对其进行评估。选择哌醋甲酯（MPH）作为 hCES1 的选择性底物。使用先前开发的细胞系进行了体外研究，这些细胞系过表达 hCES1，p-硝基苯乙酸酯和 d-MPH 均作为已知底物。阿立哌唑、奋乃静、硫利达嗪和氟西汀被确定为强效 hCES1 抑制剂。随后进行了一项补充的动物研究，以进一步评估阿立哌唑对 FVB 小鼠 CES1 活性的抑制作用。结果表明，同时给予外消旋（即 dl-）MPH 和阿立哌唑会显著增加两种总 MPH 以及活性较低的 l-异构体的血浆浓度。与对照动物相比，用阿立哌唑处理的小鼠中 d-MPH 和 l-MPH 的血浆浓度比显著降低，表明阿立哌唑处理动物的 CES1 催化活性总体降低。此外，基于定量构效关系的分析确定了一些 CES1 抑制剂的结构相似性。总之，与 MPH 的药物相互作用可能是由于同时进行药物治疗而通过 CES1 抑制介导的。CES1 抑制代表了 MPH 处置、耐受性和反应中被忽视且研究甚少的变异性来源。
