RESUMO
AIMS: A large interindividual variability in plasma concentrations has been reported in patients treated with donepezil, the most frequently prescribed antidementia drug. We aimed to evaluate clinical and genetic factors influencing donepezil disposition in a patient population recruited from a naturalistic setting. METHODS: A population pharmacokinetic study was performed including data from 129 older patients treated with donepezil. The patients were genotyped for common polymorphisms in the metabolic enzymes CYP2D6 and CYP3A, in the electron transferring protein POR and the nuclear factor NR1I2 involved in CYP activity and expression, and in the drug transporter ABCB1. RESULTS: The average donepezil clearance was 7.3 l h(-1) with a 30% interindividual variability. Gender markedly influenced donepezil clearance (P < 0.01). Functional alleles of CYP2D6 were identified as unique significant genetic covariate for donepezil clearance (P < 0.01), with poor metabolizers and ultrarapid metabolizers demonstrating, respectively, a 32% slower and a 67% faster donepezil elimination compared with extensive metabolizers. CONCLUSION: The pharmacokinetic parameters of donepezil were well described by the developed population model. Functional alleles of CYP2D6 significantly contributed to the variability in donepezil disposition in the patient population and should be further investigated in the context of individual dose optimization to improve clinical outcome and tolerability of the treatment.
Assuntos
Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Indanos/farmacocinética , NADPH-Ferri-Hemoproteína Redutase/genética , Piperidinas/farmacocinética , Receptores de Esteroides/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos Transversais , Donepezila , Feminino , Genótipo , Humanos , Indanos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Piperidinas/efeitos adversos , Receptor de Pregnano XRESUMO
BACKGROUND AND OBJECTIVE: Memantine, a frequently prescribed anti-dementia drug, is mainly eliminated unchanged by the kidneys, partly via tubular secretion. Considerable inter-individual variability in plasma concentrations has been reported. We aimed to investigate clinical and genetic factors influencing memantine disposition. METHODS: A population pharmacokinetic study was performed including data from 108 patients recruited in a naturalistic setting. Patients were genotyped for common polymorphisms in renal cation transporters (SLC22A1/2/5, SLC47A1, ABCB1) and nuclear receptors (NR1I2, NR1I3, RXR, PPAR) involved in transporter expression. RESULTS: The average clearance was 5.2 L/h with a 27 % inter-individual variability (percentage coefficient of variation). Glomerular filtration rate (p = 0.007) and sex (p = 0.001) markedly influenced memantine clearance. NR1I2 rs1523130 was identified as the unique significant genetic covariate for memantine clearance (p = 0.006), with carriers of the NR1I2 rs1523130 CT/TT genotypes presenting a 16 % slower memantine elimination than carriers of the CC genotype. CONCLUSION: The better understanding of inter-individual variability of memantine disposition might be beneficial in the context of individual dose optimization.
Assuntos
Demência/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Memantina/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Proteínas de Transporte/genética , Receptor Constitutivo de Androstano , Demência/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/sangue , Feminino , Genótipo , Humanos , Masculino , Memantina/sangue , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , Modelos Biológicos , Polimorfismo Genético , Receptores Citoplasmáticos e Nucleares/genéticaRESUMO
BACKGROUND: Vocally disruptive behavior (VDB) in the elderly is a common condition, especially in people with dementia, but difficult to treat. It may occur in as many as 40% of nursing home residents. This study is a review of the existing literature on this condition. METHOD: The literature review was conducted using PubMed (particularly Medline and the Cochrane database) and reference lists from relevant publications in English, French, and German. RESULTS: Most studies are small and no conclusive prevalence data are available. Many biological and psychosocial treatments have been advocated, but most studies are little more than anecdotal case reports. It is evident that VDB can have deleterious consequences on others and the patients themselves, although no studies specifically examine the range or the pervasiveness of VDB. Etiopathogenic research on VDB is still in its infancy. CONCLUSIONS: Most aspects surrounding VDB are insufficiently understood. The heterogeneity and multiple contributive factors regarding VDB suggest quite convincingly that a panoply of different interventions tailored to the individual's needs will be required to overcome VDB and the suffering related to it.
