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

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.