title: Investigating the binding interactions of the anti-Alzheimer's drug donepezil with CYP3A4 and P-glycoprotein.
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±1.00μM) whereas the reference agent ketoconazole exhibited potent inhibition (CYP3A4 IC50=0.20±0.01μM). P-gp inhibition studies indicate that donepezil exhibits better inhibition relative to CYP3A4 (P-gp EC50=34.85±4.63μM) although it was less potent compared to ketoconazole (P-gp EC50=9.74±1.23μM). At higher concentrations, donepezil exhibited significant inhibition of CYP3A4 (69%, 84% and 87% inhibition at 100, 250 and 500μM, 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 -4.91kcal/mol, respectively) compared to the ketoconazole-CYP3A4 and P-gp complex (CDOCKER energies=-41.89 and -20.03kcal/mol, respectively).
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Alanna
authors.initials: A
authors.lastname: McEneny-King
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Edginton
authors.affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada. Electronic address: praopera@uwaterloo.ca.
authors.forename: Praveen P N
authors.initials: PP
authors.lastname: Rao
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D000077265:Donepezil; D004347:Drug Interactions; D006801:Humans; D007189:Indans / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D018697:Nootropic Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human