Pharmacogenetic Aspects of Therapy with Cholinesterase Inhibitors: The Role of CYP2D6 in Alzheimers Disease Pharmacogenetics

Abstract

Recent studies demonstrate that the therapeutic response in Alzheimer's disease (AD) is genotype-specific. More than 200 genes are potentially associated with AD pathogenesis and neurodegeneration, and approximately 1,400 genes distributed across the human genome account for 20 to 95% of variability in drug disposition and pharmacodynamics. Cytochrome P450 enzymes encoded by genes of the CYP superfamily, such as CYP1A1 (15q22-q24), CYP2A6 (19q13.2), CYP2C8 (10q24), CYP2C9 (10q24), CYP2C19 (10q24.1-q24.3), CYP2D6 (22q13.1), CYP2E1 (10q24.3-qter), and CYP3A5 (7q22.1), acting as terminal oxidases in multicomponent electron transfer chains which are called P450-containing monooxygenase systems, metabolize more than 90% of drugs. Some of the enzymatic products of the CYP gene superfamily can share substrates, inhibitors and inducers whereas others are quite specific for their substrates and interacting drugs. Some cholinesterase inhibitors (tacrine, donepezil, galantamine) are metabolized via CYP-related enzymes, especially CYP2D6, CYP3A4, and CYP1A2. The distribution of CYP2D6 genotypes in the Spanish population is the following: (a) Extensive Metabolizers (EM)(51.61%): *1/*1, 47.10%; and *1/*10, 4.52%; (b) Intermediate Metabolizers (IM)(32.26%): *1/*3, 1.95%; *1/*4, 17.42%; *1/*5, 3.87%; *1/*6, 2.58%; *1/*7, 0.75%; *10/*10, 1.30%; *4/*10, 3.23%; *6/*10, 0.65%; and *7/*10, 0.65%; (b) Poor Metabolizers (PM)(9.03%): *4/*4, 8.37%; and *5/*5, 0.65%; and (c) Ultrarapid Metabolizers (UM)(7.10%): *1xN/*1, 4.52%; *1xN/*4, 1.95%; and CYP2D6 gene duplications, 0.65%. PMs and UMs also accumulate genotypes of risk associated with APOE-, PS-, ACE-, and PRNP-related genes. Approximately, 15% of the AD population may exhibit an abnormal metabolism of cholinesterase inhibitors; about 50% of this population cluster would show an ultrarapid metabolism, requiring higher doses of cholinesterase inhibitors to reach a therapeutic threshold, whereas the other 50% of the cluster would exhibit a poor metabolism, displaying potential adverse events at low doses. In AD patients treated with a multifactorial therapy, including cholinesterase inhibitors (e.g., donepezil), the best responders are the CYP2D6-related EMs and IMs, and the worst responders are PMs and UMs. In addition, the presence of the APOE-4 allele in genetic clusters integrating CYP2D6 and APOE genotypes contributes to deteriorate the therapeutic outcome. From these data, it can be postulated that pharmacogenetic and pharmacogenomic factors are responsible for 75-85% of the therapeutic response in AD patients treated with conventional drugs.

APOE-TOMM40 in the Pharmacogenomics of Dementia

“…From studies designed to define APOE-related AD phenotypes, several conclusions can be drawn: (i) the age-at-onset is 5-10 years earlier in approximately 80% of AD cases harboring the APOE-4/4 genotype; brain atrophy and AD neuropathology is markedly increased in APOE-4/4>APOE-3/4>APOE-3/3; (xi) brain mapping activity shows a significant increase in slow wave activity in APOE-4/4 from early stages of the disease; (xii) brain hemodynamics, as reflected by reduced brain blood flow velocity and increased pulsatility and resistance indices, is significantly worse in APOE-4/4 (and in APOE-4 carriers in general, as compared with APOE-3 carriers); brain hypoperfusion and neocortical oxygenation is also more deficient in APOE-4 carriers; (xiii) lymphocyte apoptosis is markedly enhanced in APOE-4 carriers; (xiv) cognitive deterioration is faster in APOE-4/4 patients than in carriers of any other APOE genotype; (xv) in approximately 3-8% of the AD cases, the presence of some dementia-related metabolic dysfunctions accumulates more in APOE-4 carriers than in APOE-3 carriers; (xvi) some behavioral disturbances, alterations in circadian rhythm patterns, and mood disorders are slightly more frequent in APOE-4 carriers; (xvii) aortic and systemic atherosclerosis is also more frequent in APOE-4 carriers; (xviii) liver metabolism and transaminase activity also differ in APOE-4/4 with respect to other genotypes; (xix) hypertension and other cardiovascular risk factors also accumulate in APOE-4; and (xx) APOE-4/4 carriers are the poorest responders to conventional drugs. These 20 major phenotypic features clearly illustrate the biological disadvantage of APOE-4 homozygotes and the potential consequences that these patients may experience when they receive pharmacological treatment for AD and/or concomitant pathologies [1][2][3][4][5][18][19][20][21][22][23][24][25][26][27][28][29][30][77][78][79]. In our study, it is clear that APOE-4 carriers are the worst responders to conventional treatments Figures 3 and 4.…”

“…The effect of CDP-choline, either alone or in combination with donepezil, as well as the effects of sardilipin, are APOE-dependent [3,[18][19][20][21][22][23][24][25][26][27][28]. In our study, the administration of cholinesterase inhibitors was avoided in 1M 3M 6M 9M 12M BL 1M 3M 6M 9M 12M BL 1M 3M 6M 9M 12M BL 1M 3M 6M 9M 12M BL 1M 3M 6M 9M 12M BL 1M 3M 6M 9M order to eliminate distorting variability and side-effects associated with CYP2D6-related factors [25,27,75].…”

“…APOE-4 may influence AD pathology by interacting with APP metabolism and Aβ accumulation, enhancing hyperphosphorylation of tau protein and neurofibrillary tangles (NFT) formation, reducing choline acetyltransferase activity, increasing oxidative processes, modifying inflammation-related neuroimmunotrophic activity and glial activation, altering lipid metabolism, lipid transport and membrane biosynthesis in sprouting and synaptic remodeling, and inducing neuronal apoptosis [5,[18][19][20][21]. In addition, multiple studies over the past two decades have demonstrated that APOE variants may affect the therapeutic response to anti-dementia drugs [20][21][22][23][24][25][26][27][28][29][30].…”

Doping for Chess Performance

“…For the AChEIs, extensive metabolizers of drugs as defined by gene variations in cytochrome P450 (a family of degradative enzymes) might show greater response to donepezil and rivastigmine [182,183].…”

Forensic Pharmacogenetics

“…EMs and IMs are the best responders, and PMs and UMs are the worst responders to pharmacologic treatments in AD. At this early stage of the development of pharmacogenomic/pharmacogenetic procedures in AD therapeutics, it seems very plausible that the pharmacogenetic response in Alzheimer's disease depends on the interaction of genes involved in drug metabolism and genes associated with Alzheimer's disease pathogenesis (Cacabelos, 2007). Paracetamol and tramadol were the most popular analgesics among individuals taking warfarin.…”