The administration of donepezil hydrochloride concomitantly with other cholinesterase inhibitors should be avoided. Donepezil hydrochloride and its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine, digoxin, thioridazine, risperidone, and sertraline in humans. The metabolism of donepezil hydrochloride is not affected by concurrent administration of digoxin, cimetidine, thioridazine, risperidone and sertraline. In a study of Parkinson’s disease patients on optimal treatment with L-dopa/carbidopa, administration of donepezil hydrochloride for 21 days had no effects on L-dopa or carbidopa blood levels. In this study, no effects on motor activity were observed. In vitro studies have shown that the cytochrome P450 isoenzymes 3A4 and to a minor extent 2D6 are involved in the metabolism of donepezil. Drug interaction studies performed in vitro show that ketoconazole and quinidine, known inhibitors of CYP3A4 and CYP2D6 respectively, inhibit donepezil metabolism. Therefore these and other CYP3A4 inhibitors, such as itraconazole and erythromycin, and CYP2D6 inhibitors, such as fluoxetine could inhibit the metabolism of donepezil. In a study in healthy volunteers, ketoconazole increased mean donepezil concentrations by about 30%. These increases are smaller than those produced by ketoconazole for other agents sharing the CYP3A4 pathway. Administration of donepezil had no effect on the pharmacokinetics of ketoconazole.
The influence of CYP2D6 on donepezil clearance was further explored via population pharmacokinetic (PK) analysis in a controlled clinical study of donepezil 10 mg in patients with moderately severe to severe AD. In the PK database for Study 326, there were 31patients classified as poor metabolizers, 508 patients classified as extensive metabolizers, 13 patients classified as ultra-rapid metabolizers, and 298 patients whose CYP2D6 phenotype was not classified. The largest subtype was the extensive metabolizer group and was used as the reference group. Small differences in clearance values were observed among the CYP2D6 subgroups. When compared to the extensive metabolizers, the poor metabolizer group had a 31.5% lower clearance, and the ultra-rapid metabolizer group had a 24% higher clearance. While the differences among groups were relatively small, the results indicate that donepezil is eliminated, in part, via CYP2D6 metabolism. Overall, these results suggest that CYP2D6 does not significantly contribute to the metabolism of donepezil.
Based on in vitro studies, donepezil shows little or no evidence of direct inhibition of CYP2B6, CYP2C8 and CYP2C19 at clinically relevant concentrations.
Enzyme inducers, such as rifampicin, phenytoin, carbamazepine, and alcohol may reduce the levels of donepezil. Since the magnitude of an inhibiting or inducing effect is unknown, such drug combinations should be used with care. Donepezil hydrochloride has the potential to interfere with medications having anticholinergic activity. There is also the potential for synergistic activity with concomitant treatment involving such medications as succinylcholine and other neuromuscular blocking agents. There is also a potential for synergistic activity with cholinergic agonists or beta blocking agents which have effects on cardiac conduction. Donepezil was not a substrate of P-glycoprotein in an in vitro study.