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Donepezil plasma concentrations, CYP2D6 and CYP3A4 phenotypes, and cognitive outcome in Alzheimer’s disease

  • Pharmacokinetics and Disposition
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Abstract

Purpose

The purpose of the study is to evaluate whether donepezil (D) plasma concentrations and activity of CYP2D6 and CYP3A4 are associated with the therapeutic response of patients with mild to moderate Alzheimer’s disease (AD).

Methods

This study comprised 54 patients affected by probable AD in therapy with D 10 mg/daily for at least 3 months. Plasma concentrations of D and its three main metabolites (6DD, 5DD, DNox) were assayed with a novel high performance liquid chromatography (HPLC) technique. Cognitive progression was assessed at baseline and at 9 months of follow-up with the mini mental state examination (MMSE). The activities of the two cytochromes involved in D metabolism—CYP2D6 and CYP3A4—were evaluated according to their metabolic ratios in plasma or urine, after test doses of probe drugs (dextromethorphan and omeprazole).

Results

A significant correlation was found between plasma levels of D and variations in MMSE scores after 9 months of therapy (r 2 = 0.14; p = 0.006). Neither the concentrations of D metabolites nor the metabolic ratios of CYP2D6 and CYP3A4 showed any correlations with cognitive variations. Low CYP2D6 activity and advanced age were associated with high D concentrations. Patients who were treated with CYP2D6 and P-glycoprotein (P-gp) inhibitors also had higher D plasma levels (mean difference = 19.6 ng/mL; p = 0.01) than those who were not.

Conclusions

D plasma concentrations, but not cytochrome phenotyping, are associated with cognitive outcomes in AD patients.

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References

  1. Raschetti R, Maggini M, Sorrentino GC, Martini N, Caffari B, Vanacore N (2005) A cohort study of effectiveness of acetylcholinesterase inhibitors in Alzheimer’s disease. Eur J Clin Pharmacol 61:361–368

    Article  CAS  PubMed  Google Scholar 

  2. Tiseo PJ, Perdomo CA, Friedhoff LT (1998) Metabolism of 14C-donepezil in healthy volunteers: a single-dose study. Br J Clin Pharmacol 46(I):19–24

    CAS  PubMed  PubMed Central  Google Scholar 

  3. FDA. Highlights of prescribing information. ARICEPT®. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory. Accessed December 2014

  4. Riyath AA, Ammar BB, Faris TA (2011) In vitro kinetic study of donepezil N-oxide metabolites. Irq J Pharm 11:1–9

    Google Scholar 

  5. Jann MW, Shirley KL, Small GW (2002) Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clin Pharmacokinet 41:719–739

    Article  CAS  PubMed  Google Scholar 

  6. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT (1998) A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. D study group. Neurology 5:136–145

    Article  Google Scholar 

  7. Baumann P, Hiemke C, Ulrich S, Eckermann G, Gaertner I, Gerlach M, Kuss HJ, Laux G, Müller-Oerlinghausen B, Rao ML, Riederer P, Zernig G (2004) The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry 37:243–265

    Article  CAS  PubMed  Google Scholar 

  8. Hefner G, Brueckner A, Hiemke C, Fellgiebel A (2015) Therapeutic drug monitoring for patients with Alzheimer’s dementia to improve treatment with D. Ther Drug Monit 37:353–361

    Article  CAS  PubMed  Google Scholar 

  9. Cacabelos R (2007) D in Alzheimer’s disease: from conventional trials to pharmacogenetics. Neuropsychiatr Dis Treat 3:303–333

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Magliulo L, Dahl ML, Lombardi G, Fallarini S, Villa LM, Biolcati A, Scordo MG (2011) Do CYP3A4 and ABCB1 genotypes influence the plasma concentration and clinical outcome of donepezil treatment? Eur J Clin Pharmacol 67:47–54

    Article  CAS  PubMed  Google Scholar 

  11. Varsaldi F, Miglio G, Scordo MG, Dahl ML, Villa LM, Biolcati A, Lombardi G (2006) Impact of CYP2D6 polymorphism on steady-state plasma concentrations and clinical outcome of donepezil in Alzheimer’s disease patients. Eur J Clin Pharmacol 62:721–726

    Article  CAS  PubMed  Google Scholar 

  12. Pilotto A, Franceschi M, D’Onofrio G, Bizzarro A, Mangialasche F, Cascavilla L, Paris F, Matera MG, Pilotto A, Daniele A, Mecocci P, Masullo C, Dalla Piccola B, Seripa D (2009) Effect of a CYP2D6 polymorphism on the efficacy of donepezil in patients with Alzheimer disease. Neurology 73:761–767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Seripa D, Bizzarro A, Pilotto A, D’onofrio G, Vecchione G, Gallo AP, Cascavilla L, Paris F, Grandone E, Mecocci P, Santini SA, Masullo C, Pilotto A (2011) Role of cytochrome P4502D6 functional polymorphisms in the efficacy of donepezil in patients with Alzheimer’s disease. Pharmacogenet Genomics 21:225–230

    CAS  PubMed  Google Scholar 

  14. Noetzli M, Guidi M, Ebbing K, Eyer S, Wilhelm L, Michon A, Thomazic V, Stancu I, Alnawaqil AM, Bula C, Zumbach S, Gaillard M, Giannakopoulos P, von Gunten A, Csajka C, Eap CB (2014) Population pharmacokinetic approach to evaluate the effect of CYP2D6, CYP3A4, ABCB1, POR and NR112 genotypes on donepezil clearance. Br J Clin Pharmacol 78:135–144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: repost of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 34:939–944

    Article  CAS  PubMed  Google Scholar 

  16. Zhou SF, Xue CC, Yu XQ, Li C, Wang G (2007) Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit 29:687–710

    Article  CAS  PubMed  Google Scholar 

  17. Spina E, Santoro V, D’Arrigo C (2008) Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther 30:1206–1227

    Article  CAS  PubMed  Google Scholar 

  18. O’Brien FE, Dinan TG, Griffin BT, Cryan JF (2012) Interactions between antidepressants and P-glycoprotein at the blood–brain barrier: clinical significance of in vitro and in vivo findings. Br J Pharmacol 165:289–312

    Article  PubMed  PubMed Central  Google Scholar 

  19. Folstein MF, Folstein SE, McHugh PR (1976) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198

    Article  Google Scholar 

  20. Katz S, Akpom CA (1976) A measure of primary sociobiological functions. Int J Health Serv 6:493–508

    Article  CAS  PubMed  Google Scholar 

  21. Lawton MP, Brody EM (1969) Assessment of older people: self maintaining and instrumental activities of daily living. Gerontologist 9:179–186

    Article  CAS  PubMed  Google Scholar 

  22. De Rui M, Coin A, Granziera S, Girardi A, Catanzaro S, Manzato E, Perissinotto E, Sergi G (2014) Short- and long-term efficacy of cholinesterase inhibitors in older adults with Alzheimer’s disease and mixed dementia: results of a 21-month observational study. Panminerva Med. Jul 16

  23. Groppa F, Coin A, De Rosa G, Granziera S, Alexopoulos C, Pamio MV, Padrini R (2016) Monitoring plasma levels of donepezil, 5-O-desmethyl-D, 6-O-desmethyl-D, and D-N-oxide by a novel HPLC method in patients with Alzheimer disease. Ther Drug Monit 38:108–113

    Article  CAS  PubMed  Google Scholar 

  24. Rebsamen MC, Desmeules J, Daali Y, Chiappe A, Diemand A, Rey C, Chabert J, Dayer P, Hochstrasser D, Rossier MF (2009) The AmpliChip CYP450 test: cytochrome P450 2D6 genotype assessment and phenotype prediction. Pharmacogenomics J 9:34–41

    Article  CAS  PubMed  Google Scholar 

  25. Bottiger Y (2006) Use of omeprazole sulfone in a single plasma sample as a probe for CYP3A4. Eur J Clin Pharmacol 62:621–5

    Article  PubMed  Google Scholar 

  26. Flores-Perez J, Flores-Perez C, Juarez-Olguin H, Lares-Asseff I, Sosa-Macias M (2004) Determination of dextrometorphan and dextrorphan in human urine by high performance liquid chromatography for pharmacogenetic investigations. Chromatographia 59:481–485

    Article  CAS  Google Scholar 

  27. Gonzalez HM, Romero EM, Chavez T de J, Peregrina AA, Quezada V, Hoyo-Vadillo C (2002) Phenotype of CYP2C9 and CYP3A4 by determination of omeprazole and its two metabolites in plasma using liquid chromatography with liquid-liquid extraction. J Chromatogr B 780:459–465

    Article  CAS  Google Scholar 

  28. Cohen J (1988) Statistical power analysis for the behavioral sciences, 3rd edn. Lawrence Earlbaum Associates, Hillisdale, NJ

    Google Scholar 

  29. Rogers SL, Friedhoff LT, The Donepezil Study Group (1996) The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US multicenter, randomized, double-blind, placebo-controlled trial. Dementia 7:293–303

  30. Yang YH, Chen CH, Chou MC, Li CH, Liu CK, Chen SH (2013) Concentration of donepezil to the cognitive response in Alzheimer disease. J Clin Psychopharmacol 33:351–355

    Article  PubMed  Google Scholar 

  31. Cummings JL, Geldmacher D, Farlow M, Sabbagh M, Christensen D, Betz P (2013) High-dose D (23 mg/day) for the treatment of moderate and severe Alzheimer’s disease: drug profile and clinical guidelines. CNS Neurosci Ther 19:294–301

    Article  CAS  PubMed  Google Scholar 

  32. Chianella C, Gragnaniello D, Maisano Delser P, Visentini MF, Sette E, Tola MR, Barbujani G, Fuselli S (2011) BCHE and CYP2D6 genetic variation in Alzheimer’s disease patients treated with cholinesterase inhibitors. Eur J Clin Pharmacol 67:1147–1157

    Article  CAS  PubMed  Google Scholar 

  33. Klimkowicz-Mrowiec A, Wolkow P, Sado M, Dziubek A, Pera J, Dziedzic T, Szczudlik A, Slowik A (2013) Influence of rs1080985 single nucleotide polymorphism of the CYP2D6 gene on response to treatment with donepezil in patients with Alzheimer disease. Neuropsychiatr Dis Treat 9:1029–1033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Geriatric Clinic, Department of Medicine DIMED, School of Medicine, University of Padova, 35128, Padova, Italy

    A Coin, M V Pamio, C Alexopoulos, S Granziera, A. Girardi, G. Sergi & E. Manzato

  2. Clinical Pharmacology Unit, Department of Medicine DIMED, School of Medicine, University of Padova, 35128, Padova, Italy

    F Groppa, G de Rosa & R Padrini

Authors
  1. A Coin
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  2. M V Pamio
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  3. C Alexopoulos
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  4. S Granziera
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  5. F Groppa
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  6. G de Rosa
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  7. A. Girardi
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  8. G. Sergi
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  9. E. Manzato
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  10. R Padrini
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Corresponding author

Correspondence to R Padrini.

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Funding

The study was funded by the University of Padova, Italy (Fondi “ex-60%”, 2013).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study was approved by the Ethics Committee of Azienda–ULSS 16, Padova Protocol n° 8793). All procedures in this study were in accordance with the 1964 Helsinki Declaration and its later amendments.

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Coin, A., Pamio, M.V., Alexopoulos, C. et al. Donepezil plasma concentrations, CYP2D6 and CYP3A4 phenotypes, and cognitive outcome in Alzheimer’s disease. Eur J Clin Pharmacol 72, 711–717 (2016). https://doi.org/10.1007/s00228-016-2033-1

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  • DOI: https://doi.org/10.1007/s00228-016-2033-1

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