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

Autor: Yu J; College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea., Ryu JH; College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea., Chi YH; College of Pharmacy, Sunchon National University, Suncheon-si, Republic of Korea., Paik SH; College of Pharmacy, Sunchon National University, Suncheon-si, Republic of Korea. Electronic address: shwhite@scnu.ac.kr., Kim SK; College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea. Electronic address: sangkim@cnu.ac.kr.
Jazyk: angličtina
Zdroj: Toxicology in vitro : an international journal published in association with BIBRA [Toxicol In Vitro] 2024 Oct; Vol. 100, pp. 105922. Date of Electronic Publication: 2024 Aug 22.
DOI: 10.1016/j.tiv.2024.105922
Abstrakt: 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 50 value of 22.6 μM but not by donepezil. After pre-incubating HLMs with tadalafil and NADPH, the tadalafil IC 50 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that influenced the work reported in this paper.
(Copyright © 2024. Published by Elsevier Ltd.)
Databáze: MEDLINE
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