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Do CYP3A and ABCB1 genotypes influence the plasma concentration and clinical outcome of donepezil treatment?

  • Pharmacogenetics
  • Published:
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Abstract

Purpose

The aim of our study was to evaluate the impact of CYP3A4, CYP3A5, and ABCB1 polymorphisms on donepezil disposition and clinical outcome.

Methods

Fifty-four Italian patients diagnosed with probable mild to moderate Alzheimer’s disease, treated with donepezil (37 patients 5 mg/day, 17 patients 10 mg/day) were genotyped for CYP3A4 (*1B, *3, and *4), CYP3A5 (*2, *3, and *6) and ABCB1 (3435C>T, 2677G>T/A, and 1236C>T) polymorphisms. All patients were evaluated for the degree of cognitive impairment with Mini Mental State Examination (MMSE) screening test at baseline (before treatment) and after at least 3 months of donepezil treatment at stable dose, when the drug plasma levels were measured.

Results

Three patients carried one detrimental CYP3A4 allelic variant, and 12 carried one functional CYP3A5*1 allele. No statistically significant association was found between CYP3A4 or CYP3A5 genotypes and plasma donepezil concentrations, or between genotypes and clinical response (as measured by change in MMSE score). Nine ABCB1 haplotypes were observed, the most common being 1236C/2677G/3435C (46%) and 1236T/2677T/3435T (41%). Patients homozygous for the T/T/T haplotype had slightly though not significantly lower plasma donepezil concentration-to-dose ratios than those carrying other genotypes [median (95% CI) 0.18 (0.13–0.45) vs. 0.31 (0.30–0.44) mg/l/mg/kg, respectively]. These patients also showed a slightly better clinical response (as measured by change in MMSE score) than the other genotype groups [median (95% CI) 0 (−1.3 to 3.3) vs. −1.0 (−2.1 to 0.0), respectively].

Conclusions

Our data suggest that the CYP3A4 and CYP3A5 polymorphisms are unlikely to influence donepezil metabolism and/or clinical outcome. On the other hand, the ABCB1 polymorphisms may play a role in donepezil disposition and clinical outcome.

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Acknowledgements

This work was supported by grants from the Swedish Society of Medicine, the Swedish Research Council, and the “Piedmont County Grants for Research” (2008, Turin, Italy). We thank Dr. Norio Yasui-Furukori (Hirosaki University, School of Medicine, Japan) for the generous gift of donepezil.

The study protocol was approved by the Research Ethics Committee at the “Ospedale Maggiore della Carità” of Novara (Italy) in accordance with the ethical standards laid down in the Declaration of Helsinki.

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Authors and Affiliations

  1. DISCAFF Department, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

    Laura Magliulo, Grazia Lombardi & Silvia Fallarini

  2. Department of Medical Sciences, Clinical Pharmacology, University of Uppsala, Akademiska sjukhuset, Ing. 61, 75185, Uppsala, Sweden

    Laura Magliulo, Marja-Liisa Dahl & Maria Gabriella Scordo

  3. Geriatric Clinical Unit, Ospedale Maggiore della Caritá, Novara, Italy

    Laura Maria Villa & Aldo Biolcati

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  1. Laura Magliulo
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  2. Marja-Liisa Dahl
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Correspondence to Maria Gabriella Scordo.

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Magliulo, L., Dahl, ML., Lombardi, G. et al. Do CYP3A and ABCB1 genotypes influence the plasma concentration and clinical outcome of donepezil treatment?. Eur J Clin Pharmacol 67, 47–54 (2011). https://doi.org/10.1007/s00228-010-0883-5

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  • DOI: https://doi.org/10.1007/s00228-010-0883-5

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