title: CYP2A6 genetic variation and dexmedetomidine disposition.
abstract: OBJECTIVE
  There is a large interindividual variability in dexmedetomidine dose requirements for sedation of patients in intensive care units (ICU). Cytochrome P450 2A6 (CYP2A6) mediates an important route of dexmedetomidine metabolism, and genetic variation in CYP2A6 affects the clearance of other substrate drugs. We examined whether CYP2A6 genotypes affect dexmedetomidine disposition.
  
  
  METHODS
  In 43 critically ill ICU patients receiving dexmedetomidine infusions adjusted to achieve the desired level of sedation, we determined a median of five plasma dexmedetomidine concentrations each. Forty subjects were genotyped for five common CYP2A6 alleles and grouped into normal (n = 33), intermediate (n = 5), and slow metabolizers (n = 2).
  
  
  RESULTS
  Using a Bayesian hierarchical nonlinear mixture model, estimated dexmedetomidine clearance was 49.1 L/h (posterior mean; 95% credible interval 41.4-57.6 L/h). There were no significant differences in dexmedetomidine clearance among normal, intermediate, and slow CYP2A6 metabolizer groups.
  
  
  CONCLUSIONS
  Genetic variation in CYP2A6 does not appear to be an important determinant of dexmedetomidine clearance in ICU patients.
authors.affiliation: Departments of Medicine and Pharmacology, Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Utkarsh
authors.initials: U
authors.lastname: Kohli
authors.forename: Pratik
authors.initials: P
authors.lastname: Pandharipande
authors.forename: Mordechai
authors.initials: M
authors.lastname: Muszkat
authors.forename: Gbenga G
authors.initials: GG
authors.lastname: Sofowora
authors.forename: Eitan A
authors.initials: EA
authors.lastname: Friedman
authors.forename: Mika
authors.initials: M
authors.lastname: Scheinin
authors.forename: Alastair J J
authors.initials: AJ
authors.lastname: Wood
authors.forename: E Wesley
authors.initials: EW
authors.lastname: Ely
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.forename: Leena
authors.initials: L
authors.lastname: Choi
authors.forename: C Michael
authors.initials: CM
authors.lastname: Stein
authors.forename: Daniel
authors.initials: D
authors.lastname: Kurnik
mesh_terms: D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001499:Bayes Theorem; D065637:Cytochrome P-450 CYP2A6; D020927:Dexmedetomidine / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006993:Hypnotics and Sedatives / Q000097:blood / Q000493:pharmacokinetics*; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged
chemical_list: D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6