title: Characterization of hepatic enzyme activity in older adults with dementia: potential impact on personalizing pharmacotherapy.
abstract: OBJECTIVE
  To determine the frequency of pharmacogenomic variants and concurrent medications that may alter the efficacy and tolerability of acetylcholinesterase inhibitors (AChEIs).
  
  
  METHODS
  A multisite cross-sectional study was carried out across four memory care practices in the greater Indianapolis area. Participants were adults aged 65 years and older with a diagnosis of probable or possible Alzheimer's disease (AD) (n=105). Blood samples and self-reported medication data were collected. Since two of the three AChEIs are metabolized by cytochrome P450 (CYP)-2D6, we determined the frequency of functional genetic variants in the CYP2D6 gene and calculated their predicted CYP2D6-activity scores. Concurrent medication data were collected from self-reported medication surveys, and their predicted effect on the pharmacokinetics of AChEIs was determined based on their known effects on CYP2D6 and CYP3A4/5 enzyme activities.
  
  
  RESULTS
  Among the 105 subjects enrolled, 72% were female and 36% were African American. Subjects had a mean age of 79.6 years. The population used a mean of eight medications per day (prescription and nonprescription). The CYP2D6 activity score frequencies were 0 (3.8%), 0.5 (4.8%), 1.0 (36.2%), 1.5-2.0 (51.4%), and >2.0 (3.8%). Nineteen subjects (18.1%) used a medication considered a strong or moderate inhibitor of CYP2D6, and eight subjects (7.6%) used a medication considered a strong or moderate inhibitor of CYP3A4/5. In total, 28.6% of the study population was predicted to have reduced activity of the CYP2D6 or CYP3A4/5 enzymes due to either genetic variants or concomitant medications.
  
  
  CONCLUSIONS
  Both pharmacogenetic variants and concurrent drug therapies that are predicted to alter the pharmacokinetics of AChEIs should be evaluated in older adults with AD. Pharmacogenetic and drug-interaction data may help personalize AD therapy and increase adherence by improving tolerability.
authors.affiliation: College of Pharmacy, Purdue University, West Lafayette, IN, USA ; Indiana University Center for Aging Research, Indiana University School of Medicine, Indianapolis, IN, USA ; Regenstrief Institute, Indiana University School of Medicine, Indianapolis, IN, USA ; Department of Pharmacy, Eskenazi Health Services, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Noll L
authors.initials: NL
authors.lastname: Campbell
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Skaar
authors.affiliation: Indiana University Center for Aging Research, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Perkins
authors.affiliation: Indiana University Center for Aging Research, Indiana University School of Medicine, Indianapolis, IN, USA ; Regenstrief Institute, Indiana University School of Medicine, Indianapolis, IN, USA ; Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Sujuan
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Lang
authors.initials: L
authors.lastname: Li
authors.affiliation: Indiana University Center for Aging Research, Indiana University School of Medicine, Indianapolis, IN, USA ; Regenstrief Institute, Indiana University School of Medicine, Indianapolis, IN, USA ; Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Babar A
authors.initials: BA
authors.lastname: Khan
authors.affiliation: Indiana University Center for Aging Research, Indiana University School of Medicine, Indianapolis, IN, USA ; Regenstrief Institute, Indiana University School of Medicine, Indianapolis, IN, USA ; Center for Innovation and Implementation Science, Indiana University, Indianapolis, IN, USA.
authors.forename: Malaz A
authors.initials: MA
authors.lastname: Boustani
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003430:Cross-Sectional Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D019338:Polypharmacy; D057285:Precision Medicine
chemical_list: D002800:Cholinesterase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D019389:Cytochrome P-450 CYP2D6; C473667:cytochrome P-450 CYP3A45
keywords: acetylcholinesterase inhibitor; dementia; pharmacogenomics