Cytochrome P450 2D6 Phenotyping in an Elderly Population With Dementia and Response to Galantamine in Dementia: A Pilot Study

Clarke, Jo-Anne; Cutler, Murray J.; Gong, Inna Y.; Schwarz, Ute I.; Freeman, David J.; Dasgupta, Monidipa

doi:10.1016/j.amjopharm.2011.07.003

Cited by 15 publications

(5 citation statements)

References 37 publications

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“…CYP2D6 variants are major determinants of galantamine pharmacokinetics, with CYP2D6-PMs presenting 45% and 61% higher dose-adjusted galantamine plasma concentrations than heterozygous and homozygous CYP2D6-EMs [120,143]; however, these pharmacokinetic changes might not substantially affect pharmacodynamics [144]. The coadministration of galantamine with CYP2D6 and CYP3A4 strong inhibitors increases its bioavailability [48,145]. Galantamine bioavailability and its therapeutic effects may be modified by interaction with foods and nutritional components [146].…”

Section: Galantaminementioning

confidence: 99%

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Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

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Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.

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Section: Galantaminementioning

confidence: 99%

“…APOE, APP, CHAT, ACHE, BCHE, CHRNA4, CHRNB2, and MAPT variants may affect rivastigmine pharmacokinetics and pharmacodynamics. CYP enzymes are not involved in the metabolism of rivastigmine [120,138,145,154]. UGT2B7-PMs show higher rivastigmine levels with a poor response to treatment [155].…”

Section: Rivastigminementioning

confidence: 99%

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Cacabelos

2020

IJMS

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“…J. Clarke и соавт. [22] провели фенотипирование 43 пациентов с БА и не выявили взаимосвязи между эффективностью проводимого лечения и активностью CYP2D6. По результатам исследования A.…”

Section: Discussionunclassified

Is it personalized treatment of dementia based on the CYP2D6 gene polymorphism possible?

Chebotareva

Левин

Markov

et al. 2018

Z. nevrol. psikhiatr. im. S.S. Korsakova

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Лечение деменции является одной из актуальных проблем современной неврологии. Применяемые в клинической практике антидементные препараты в части случаев оказываются неэффективными либо вызывают неприемлемые нежелательные явления. В рамках концепции персонализированного подхода к терапии ведется активный поиск предикторов эффективности и безопасности лечения у конкретного больного. Примерно 15-20% пациентам с болезнью Альцгеймера (БА) в силу особенностей фармакогенетики требуется применение ингибиторов холинэстеразы в дозах препарата, отличающихся от указанных в инструкции. Одна часть таких больных

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“…Major metabolic pathways are glucuronidation, Odemethyl ation, Ndemethylation, Noxidation and epimer ization [71]. Galantamine is extensively metabolized by the enzymes CYP2D6 and CYP3A and is a sub [72]; however, these pharmacokinetic changes might not substantially affect pharmaco dynamics [73]. The coadministration of galantamine with paroxetine (a CYP2D6 strong inhibitor), keto conazole (a CYP3A4 strong inhibitor) and erythro mycin increases its bioavailability [74,75].…”

Section: Pathogenic Genesmentioning

confidence: 99%

Pharmacogenetic Considerations in the Treatment of Alzheimer’s Disease

et al. 2016

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The practical pharmacogenetics of Alzheimer's disease (AD) is circumscribed to acetylcholinesterase inhibitors (AChEIs) and memantine. However, pharmacogenetic procedures should be applied to novel strategies in AD therapeutics including: novel AChEIs and neurotransmitter regulators, anti-Aβ treatments, anti-tau treatments, pleiotropic products, epigenetic drugs and combination therapies. Genes involved in the pharmacogenetic network are under the influence of the epigenetic machinery which regulates gene expression transcriptionally and post-transcriptionally, configuring the fundamentals of pharmacoepigenomics. Over 60% of AD patients present concomitant pathologies demanding additional treatments which increase the likelihood of drug-drug interactions. Lipid metabolism dysfunction is a pathogenic mechanism inherent to AD neurodegeneration. The therapeutic response to hypolipidemic compounds is influenced by the APOE and CYP genotypes. The development of novel compounds and the use of combination/multifactorial treatments require the implantation of pharmacogenomic procedures for the avoidance of ADRs and the optimization of therapeutics.

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Cytochrome P450 2D6 Phenotyping in an Elderly Population With Dementia and Response to Galantamine in Dementia: A Pilot Study

Cited by 15 publications

References 37 publications

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

Is it personalized treatment of dementia based on the CYP2D6 gene polymorphism possible?

Pharmacogenetic Considerations in the Treatment of Alzheimer’s Disease

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