Inhibitory Effects of Tricyclic Antidepressants on Human Liver Microsomal Morphine Glucuronidation: Application of IVIVE to Predict Potential Drug-Drug Interactions in Humans

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current drug metabolism Pub Date : 2024-01-05 DOI:10.2174/0113892002270594231212090958

Verawan Uchaipichat

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引用次数: 0

Abstract

Background: Tricyclic antidepressants (TCAs) are commonly co-administered with morphine as an adjuvant analgesic. Nevertheless, there remains a lack of information concerning metabolic drug-drug interactions (DDIs) resulting from TCA inhibition on morphine glucuronidation Objective: This study aimed to (i) examine the inhibitory effects of TCAs (viz., amitriptyline, clomipramine, imipramine, and nortriptyline) on human liver microsomal morphine 3- and 6-glucuronidation and (ii) evaluate the potential of DDI in humans by employing in vitro-in vivo extrapolation (IVIVE) approaches. Method: The inhibition parameters for TCA inhibition on morphine glucuronidation were derived from the in vitro system containing 2% BSA. The Ki values were employed to predict the DDI magnitude in vivo by using static and dynamic mechanistic PBPK approaches Results: TCAs moderately inhibited human liver microsomal morphine glucuronidation, with clomipramine exhibiting the most potent inhibition potency. Amitriptyline, clomipramine, imipramine, and nortriptyline competitively inhibited morphine 3- and 6-glucuronide formation with the respective Ki values of 91 ± 7.5 and 82 ± 11 μM, 23 ± 1.3 and 14 ± 0.7 μM, 103 ± 5 and 90 ± 7 μM, and 115 ± 5 and 110 ± 3 μM. Employing the static mechanistic IVIVE, a prediction showed an estimated 20% elevation in the morphine AUC when co-administered with either clomipramine or imipramine, whereas the predicted increase was

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三环类抗抑郁药对人体肝脏微粒体吗啡葡萄糖醛酸化的抑制作用：应用 IVIVE 预测人类潜在的药物相互作用

背景：三环类抗抑郁药（TCAs）通常与吗啡合用，作为辅助镇痛药。然而，关于 TCA 对吗啡葡萄糖醛酸化的抑制作用所导致的代谢性药物间相互作用（DDIs）的信息仍然缺乏：本研究旨在：(i) 研究 TCAs（即阿米替林、氯米帕明、丙咪嗪和去甲替林）对人体肝脏微粒体吗啡 3- 和 6-葡萄糖醛酸化的抑制作用；(ii) 采用体外-体内外推法（IVIVE）评估 DDI 在人体中的潜在作用。方法：从含有 2% BSA 的体外系统中得出 TCA 对吗啡葡萄糖醛酸化的抑制参数。采用静态和动态机理 PBPK 方法，利用 Ki 值预测体内 DDI 的大小：三氯乙酸类药物对人肝脏微粒体吗啡葡萄糖醛酸化作用有中度抑制作用，其中氯米帕明的抑制效力最强。阿米替林、氯米帕明、丙咪嗪和去甲替林竞争性抑制吗啡 3 和 6-葡萄糖醛酸的形成，其 Ki 值分别为 91 ± 7.5 和 82 ± 11 μM、23 ± 1.3 和 14 ± 0.7 μM、103 ± 5 和 90 ± 7 μM，以及 115 ± 5 和 110 ± 3 μM。采用静态机理 IVIVE 预测显示，与氯米帕明或丙咪嗪合用时，吗啡的 AUC 估计会升高 20%，而预测的升高幅度是

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来源期刊

Current drug metabolism 医学-生化与分子生物学

CiteScore

4.30

自引率

4.30%

发文量

审稿时长

4-8 weeks

期刊介绍： Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism. More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.