Impact of CYP2D6 and CYP3A4 Genetic Polymorphism on Combined Cholinesterase Inhibitors and Memantine Treatment in Mild to Moderate Alzheimer's Disease

Abstract

Aim: The impact of CYP2D6 and CYP3A4 polymorphism on the steady-state plasma concentrations and therapeutic outcome of donepezil monotherapy and combination therapy in Alzheimer's disease (AD) patients. Methods: A total of 38 patients for donepezil and 17 patients for donepezil and memantine therapy, aged ≥55 years, were recruited meeting inclusion and exclusion criteria. Polymerase chain reaction-restriction fragment length polymorphism was performed. The liquid chromatography-tandem mass spectrometry method was used for estimation of drug levels of donepezil and memantine. Results: Significant allele frequency was observed for CYP2D6*3 polymorphism in patients on donepezil monotherapy and combination therapy. Significant allele frequency for CYP2D6*4 was observed in the patients on donepezil monotherapy. Conclusion: CYP2D6 polymorphism, though not significant, might partially be involved in the plasma concentration of AD drug.

<p>CYP2D6 Predicts Plasma Donepezil Concentrations in a Cohort of Thai Patients with Mild to Moderate Dementia</p>

“…When the activity scores were translated into phenotypes, the participants were classified into NMs and IMs. There were no UMs or PMs in this study which was different from previous studies conducted in Italians, 25 Indian 26 and Japanese. 27 The average trough plasma donepezil concentrations for therapeutic doses of 5 or 10 mg donepezil were 25.9 and 50.6 ng/mL, respectively.…”

Clinical Response to Donepezil in Mild and Moderate Dementia: Relationship to Drug Plasma Concentration and CYP2D6 and APOE Genetic Polymorphisms

“…However, there were no differences concerning donepezil serum concentration among the three groups. In 2014, Sonali et al [34] studied 37 North Indian AD patients using donepezil in monotherapy with similar purpose. In their study, there was no significant difference in donepezil serum concentration among all CYP2D6 alleles analyzed (*2, 3, 4, 10 e 17) or in the clinical outcome.…”

Donepezil distribution in postmortem cases and potential for redistribution

“…However, phenotypes of CYP2D6 single nucleotide polymorphisms (SNPs) may be classified as poor metabolizer, intermediate metabolizer or extensive metabolizer. CYP2D6 polymorphism, though not significant, might be partially involved in the plasma concentration of DPZ [42][43][44]. In this study, cases 2 and 7 had type *10 gene (C100T), which is an intermediate metabolizer type.…”

“…DPZ is mainly metabolized by enzymes CYP3A4 and 2D6, which is produced in the liver. Polymorphisms in the CYP3A4 gene have been reported to have no influence on blood concentrations of DPZ [41,42]. However, phenotypes of CYP2D6 single nucleotide polymorphisms (SNPs) may be classified as poor metabolizer, intermediate metabolizer or extensive metabolizer.…”