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• W2066639712 endingPage "301" @default.
• W2066639712 startingPage "297" @default.
• W2066639712 abstract "The anti-Alzheimer’s agent donepezil is known to bind to the hepatic enzyme CYP3A4, but its relationship with the efflux transporter P-glycoprotein (P-gp) is not as well elucidated. We conducted in vitro inhibition studies of donepezil using human recombinant CYP3A4 and P-gp. These studies show that donepezil is a weak inhibitor of CYP3A4 (IC50 = 54.68 ± 1.00 μM) whereas the reference agent ketoconazole exhibited potent inhibition (CYP3A4 IC50 = 0.20 ± 0.01 μM). P-gp inhibition studies indicate that donepezil exhibits better inhibition relative to CYP3A4 (P-gp EC50 = 34.85 ± 4.63 μM) although it was less potent compared to ketoconazole (P-gp EC50 = 9.74 ± 1.23 μM). At higher concentrations, donepezil exhibited significant inhibition of CYP3A4 (69%, 84% and 87% inhibition at 100, 250 and 500 μM, respectively). This indicates its potential to cause drug-drug interactions with other CYP3A4 substrates upon co-administration; however, this scenario is unlikely in vivo due to the low therapeutic concentrations of donepezil. Similarly, donepezil co-administration with P-gp substrates or inhibitors is unlikely to result in beneficial or adverse drug interactions. The molecular docking studies show that the 5,6-dimethoxyindan-1-one moiety of donepezil was oriented closer to the heme center in CYP3A4 whereas in the P-gp binding site, the protonated benzylpiperidine pharmacophore of donepezil played a major role in its binding ability. Energy parameters indicate that donepezil complex with both CYP3A4 and P-gp was less stable (CDOCKER energies = −15.05 and −4.91 kcal/mol, respectively) compared to the ketoconazole-CYP3A4 and P-gp complex (CDOCKER energies = −41.89 and −20.03 kcal/mol, respectively)." @default.
• W2066639712 created "2016-06-24" @default.
• W2066639712 creator A5019411028 @default.
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• W2066639712 date "2015-01-01" @default.
• W2066639712 modified "2023-09-27" @default.
• W2066639712 title "Investigating the binding interactions of the anti-Alzheimer’s drug donepezil with CYP3A4 and P-glycoprotein" @default.
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• W2066639712 doi "https://doi.org/10.1016/j.bmcl.2014.11.046" @default.
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