Cytochrome P450-mediated metabolic interactions between donepezil and tadalafil in human liver microsomes

IF 2.6 3区医学 Q3 TOXICOLOGY Toxicology in Vitro Pub Date : 2024-08-22 DOI:10.1016/j.tiv.2024.105922

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Abstract

Donepezil and tadalafil, commonly prescribed among older persons to treat dementia and erectile dysfunction, respectively, are primarily metabolized by cytochrome P450 (CYP) 3A4. However, the drug-drug interactions (DDIs) of these drugs are unknown. Therefore, this study evaluated the CYP-mediated metabolic interaction between donepezil and tadalafil using pooled human liver microsomes (HLMs) to predict their DDI potential. Donepezil metabolism was tadalafil-concentration dependently changed in HLMs incubated with 0.1 μM donepezil and showed the maximum 32.3% increase in the donepezil half-life at 1 μM tadalafil. The formation rates of donepezil metabolites, such as N-desbenzyl donepezil and 3-hydroxy donepezil, decreased by 28.3% and 30.3%, respectively, in HLMs incubated with 1 μM tadalafil and 0.1 μM donepezil. In contrast, neither the half-life of tadalafil nor the production rate of its metabolite, desmethylene tadalafil, was changed by >20% in the presence of donepezil (up to 1 μM). CYP3A4 activity was inhibited by tadalafil with an IC₅₀ value of 22.6 μM but not by donepezil. After pre-incubating HLMs with tadalafil and NADPH, the tadalafil IC₅₀ value against CYP3A4 was approximately 7.04-fold lower, suggesting time-dependent tadalafil inhibition. This study shows that the DDI between donepezil and tadalafil is primarily due to time-dependent inhibition against CYP3A4 by tadalafil.

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细胞色素 P450 介导的多奈哌齐和他达拉非在人类肝脏微粒体中的代谢相互作用。

多奈哌齐和他达拉非分别是老年人治疗痴呆症和勃起功能障碍的常用处方药，主要通过细胞色素 P450 (CYP) 3A4 进行代谢。然而，这些药物的药物相互作用（DDI）尚不清楚。因此，本研究使用集合人肝微粒体（HLMs）评估了多奈哌齐和他达拉非之间由 CYP 介导的代谢相互作用，以预测它们的 DDI 潜力。在用 0.1 μM 多奈哌齐培养的 HLMs 中，多奈哌齐的代谢随他达拉非浓度的变化而变化，在 1 μM 他达拉非浓度下，多奈哌齐的半衰期最长增加 32.3%。在用 1 μM tadalafil 和 0.1 μM 多奈哌齐培养的 HLMs 中，N-去苄基多奈哌齐和 3-羟基多奈哌齐等多奈哌齐代谢物的形成率分别下降了 28.3% 和 30.3%。与此相反，在多奈哌齐（高达 1 μM）存在的情况下，他达拉非的半衰期及其代谢产物去亚甲基他达拉非的生成率均未发生 20% 以上的变化。他达拉非对 CYP3A4 活性有抑制作用，IC50 值为 22.6 μM，但多奈哌齐没有抑制作用。用他达拉非和 NADPH 预孵育 HLM 后，他达拉非对 CYP3A4 的 IC50 值降低了约 7.04 倍，这表明他达拉非的抑制作用具有时间依赖性。这项研究表明，多奈哌齐和他达拉非之间的 DDI 主要是由于他达拉非对 CYP3A4 的抑制具有时间依赖性。

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来源期刊

Toxicology in Vitro 医学-毒理学

CiteScore

6.50

自引率

3.10%

发文量

181

审稿时长

65 days

期刊介绍： Toxicology in Vitro publishes original research papers and reviews on the application and use of in vitro systems for assessing or predicting the toxic effects of chemicals and elucidating their mechanisms of action. These in vitro techniques include utilizing cell or tissue cultures, isolated cells, tissue slices, subcellular fractions, transgenic cell cultures, and cells from transgenic organisms, as well as in silico modelling. The Journal will focus on investigations that involve the development and validation of new in vitro methods, e.g. for prediction of toxic effects based on traditional and in silico modelling; on the use of methods in high-throughput toxicology and pharmacology; elucidation of mechanisms of toxic action; the application of genomics, transcriptomics and proteomics in toxicology, as well as on comparative studies that characterise the relationship between in vitro and in vivo findings. The Journal strongly encourages the submission of manuscripts that focus on the development of in vitro methods, their practical applications and regulatory use (e.g. in the areas of food components cosmetics, pharmaceuticals, pesticides, and industrial chemicals). Toxicology in Vitro discourages papers that record reporting on toxicological effects from materials, such as plant extracts or herbal medicines, that have not been chemically characterized.