Yu Jieun, Ryu Ji Hyeon, Chi Yong Ha, Paik Soo Heui, Kim Sang Kyum
College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
College of Pharmacy, Sunchon National University, Suncheon-si, Republic of Korea.
Toxicol In Vitro. 2024 Oct;100:105922. doi: 10.1016/j.tiv.2024.105922. Epub 2024 Aug 22.
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 IC value of 22.6 μM but not by donepezil. After pre-incubating HLMs with tadalafil and NADPH, the tadalafil IC 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.
多奈哌齐和他达拉非通常分别用于治疗老年人的痴呆症和勃起功能障碍，它们主要通过细胞色素P450（CYP）3A4代谢。然而，这些药物之间的药物相互作用（DDIs）尚不清楚。因此，本研究使用人肝微粒体（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，以预测它们发生药物相互作用的可能性。在与0.1μM多奈哌齐一起孵育的HLMs中，多奈哌齐的代谢呈他达拉非浓度依赖性变化，在1μM他达拉非时，多奈哌齐的半衰期最长增加了32.3%。在与1μM他达拉非和0.1μM多奈哌齐一起孵育的HLMs中，多奈哌齐代谢物如N-去苄基多奈哌齐和3-羟基多奈哌齐的生成率分别降低了28.3%和30.3%。相比之下，在存在多奈哌齐（高达1μM）的情况下，他达拉非的半衰期及其代谢物去甲基他达拉非的生成率变化均未超过20%。他达拉非对CYP3A4活性有抑制作用，IC值为22.6μM，而多奈哌齐对其无抑制作用。在用他达拉非和NADPH预孵育HLMs后，他达拉非对CYP3A4的IC值降低了约7.04倍，表明他达拉非存在时间依赖性抑制作用。本研究表明，多奈哌齐和他达拉非之间的药物相互作用主要是由于他达拉非对CYP3A4的时间依赖性抑制。
