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.

1.
Seltzer B: Donepezil: an update. Expert Opin Pharmacother 2007;8:1011-1023.
2.
Barner EL, Gray SL: Donepezil use in Alzheimer disease. Ann Pharmacother 1998;32:70-77.
3.
Varsaldi F, Miglio G, Scordo MG, Dahl ML, Villa LM, Biolcati A, Lombardi G: Impact of the CYP2D6 polymorphism on steady-state plasma concentrations and clinical outcome of donepezil in Alzheimer's disease patients. Eur J Clin Pharmacol 2006;62:721-726.
4.
Pilotto A, Franceschi M, D'Onofrio G, Bizzarro A, Mangialasche F, Cascavilla L, Paris F, Matera MG, Daniele A, Mecocci P, Masullo C, Dallapiccola B, Seripa D: Effect of a CYP2D6 polymorphism on the efficacy of donepezil in patients with Alzheimer disease. Neurology 2009;73:761-767.
5.
Magliulo L, Dahl ML, Lombardi G, Fallarini S, Villa LM, Biolcati A, Scordo MG: Do CYP3A and ABCB1 genotypes influence the plasma concentration and clinical outcome of donepezil treatment? Eur J Clin Pharmacol 2011;67:47-54.
6.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM: Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34:939-944.
7.
Folstein MF, Folstein SE, McHugh PR: ‘Mini-mental state'. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198.
8.
Naveen AT, Prasanna T, Farzana BL, Rajan S, Adithan C: CYP2D6 genotype and phenotype relationship in South Indians. J Postgrad Med 2006;52:253-256.
9.
Hsieh KP, Lin YY, Cheng CL, Lai ML, Lin MS, Siest JP, Huang JD: Novel mutations of CYP3A4 in Chinese. Drug Metab Dispos 2001;29:268-273.
10.
Almeida AA, Campos DR, Bernasconi G, Calafatti S, Barros FA, Eberlin MN, Meurer EC, Paris EG, Pedrazzoli J: Determination of memantine in human plasma by liquid chromatography-electrospray tandem mass spectrometry: application to a bioequivalence study. J Chromatogr B Analyt Technol Biomed Life Sci 2007;848:311-316.
11.
Apostolou C, Dotsikas Y, Kousoulos C, Loukas YL: Quantitative determination of donepezil in human plasma by liquid chromatography/tandem mass spectrometry employing an automated liquid-liquid extraction based on 96-well format plates. Application to a bioequivalence study. J Chromatogr B Analyt Technol Biomed Life Sci 2007;848:239-244.
12.
Naveen AT, Adithan C, Soya SS, Gerard N, Krishnamoorthy R: CYP2D6 genetic polymorphism in South Indian populations. Biol Pharm Bull 2006;29:1655-1658.
13.
Lamba V, Lamba JK, Dilawari JB, Kohli KK: Genetic polymorphism of CYP2D6 in North Indian subjects. Eur J Clin Pharmacol 1998;54:787-791.
14.
Aklillu E, Persson I, Bertilsson L, Johansson I, Rodrigues F, Ingelman-Sundberg M: Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1996;278:441-446.
15.
Singh M, Khanna VK, Shukla R, Parmar D: Association of polymorphism in cytochrome P450 2D6 and N-acetyltransferase-2 with Parkinson's disease. Dis Markers 2010;28:87-93.
16.
Bradford LD: CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 2002;3:229-243.
17.
Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA: Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes. J Biol Chem 1990;265:17209-17214.
18.
Kurth MC, Kurth JH: Variant cytochrome P450 CYP2D6 allelic frequencies in Parkinson's disease. Am J Med Genet 1993;48:166-168.
19.
Zanger UM, Raimundo S, Eichelbaum M: Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 2004;369:23-37.
20.
Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP: Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994;270:414-423.
21.
Rendic S, Di Carlo FJ: Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev 1997;29:413-580.
22.
Thummel KE, Wilkinson GR: In vitro and in vivo drug interactions involving human CYP3A. Annu Rev Pharmacol Toxicol 1998;38:389-430.
23.
Watkins PB: Noninvasive tests of CYP3A enzymes. Pharmacogenetics 1994;4:171-184.
24.
Dai D, Tang J, Rose R, Hodgson E, Bienstock RJ, Mohrenweiser HW, Goldstein JA: Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther 2001;299:825-831.
25.
Lamba JK, Lin YS, Schuetz EG, Thummel KE: Genetic contribution to variable human CYP3A-mediated metabolism. Adv Drug Deliv Rev 2002;54:1271-1294.
26.
Hu YF, He J, Chen GL, Wang D, Liu ZQ, Zhang C, Duan LF, Zhou HH: CYP3A5*3 and CYP3A4*18 single nucleotide polymorphisms in a Chinese population. Clin Chim Acta 2005;353:187-192.
27.
Rais N, Chawla YK, Kohli KK: CYP3A phenotypes and genotypes in North Indians. Eur J Clin Pharmacol 2006;62:417-422.
28.
Katoh Y, Uchida S, Kawai M, Takei N, Mori N, Kawakami J, Kagawa Y, Yamada S, Namiki N, Hashimoto H: Effects of cigarette smoking and cytochrome P450 2D6 genotype on fluvoxamine concentration in plasma of Japanese patients. Biol Pharm Bull 2010;33:285-288.
29.
Sonali N, Tripathi M, Sagar R, Velpandian T, Subbiah V: Clinical effectiveness of rivastigmine monotherapy and combination therapy in Alzheimer's patients. CNS Neurosci Ther 2013;19:91-97.
30.
Hesselink DA, van Gelder T: Genetic and nongenetic determinants of between-patient variability in the pharmacokinetics of mycophenolic acid. Clin Pharmacol Ther 2005;78:317-321.
31.
He P, Court MH, Greenblatt DJ, Von Moltke LL: Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin Pharmacol Ther 2005;77:373-387.
32.
Gervasini G, Carrillo JA, Benitez J: Potential role of cerebral cytochrome P450 in clinical pharmacokinetics: modulation by endogenous compounds. Clin Pharmacokinet 2004;43:693-706.
33.
Armstrong M, Daly AK, Cholerton S, Bateman DN, Idle JR: Mutant debrisoquine hydroxylation genes in Parkinson's disease. Lancet 1992;339:1017-1018.
34.
Atkinson A, Singleton AB, Steward A, Ince PG, Perry RH, McKeith IG, Fairbairn AF, Edwardson JA, Daly AK, Morris CM: CYP2D6 is associated with Parkinson's disease but not with dementia with Lewy bodies or Alzheimer's disease. Pharmacogenetics 1999;9:31-35.
35.
Smith CA, Gough AC, Leigh PN, Summers BA, Harding AE, Maraganore DM, Sturman SG, Schapira AH, Williams AC, et al: Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson's disease. Lancet 1992;339:1375-1377.
36.
Saitoh T, Xia Y, Chen X, Masliah E, Galasko D, Shults C, Thal LJ, Hansen LA, Katzman R: The CYP2D6B mutant allele is overrepresented in the Lewy body variant of Alzheimer's disease. Ann Neurol 1995;37:110-112.
37.
Tanaka S, Chen X, Xia Y, Kang DE, Matoh N, Sundsmo M, Thomas RG, Katzman R, Thal LJ, Trojanowski JQ, Saitoh T, Ueda K, Masliah E: Association of CYP2D microsatellite polymorphism with Lewy body variant of Alzheimer's disease. Neurology 1998;50:1556-1562.
38.
Yamada H, Dahl ML, Lannfelt L, Viitanen M, Winblad B, Sjoqvist F: CYP2D6 and CYP2C19 genotypes in an elderly Swedish population. Eur J Clin Pharmacol 1998;54:479-481.
39.
Zhong Y, Zheng X, Miao Y, Wan L, Yan H, Wang B: Effect of CYP2D6*10 and APOE polymorphisms on the efficacy of donepezil in patients with Alzheimer's disease. Am J Med Sci 2013;345:222-226.
40.
Tiseo PJ, Perdomo CA, Friedhoff LT: Concurrent administration of donepezil HCl and cimetidine: assessment of pharmacokinetic changes following single and multiple doses. Br J Clin Pharmacol 1998;46(suppl 1):25-29.
41.
Tiseo PJ, Rogers SL, Friedhoff LT: Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration. Br J Clin Pharmacol 1998;46(suppl 1):13-18.
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