CYP2A6 genetic variation and dexmedetomidine disposition

• Published in: European journal of clinical pharmacology Vol. 68; no. 6; pp. 937 - 942
• Main Authors: Kohli, Utkarsh, Pandharipande, Pratik, Muszkat, Mordechai, Sofowora, Gbenga G., Friedman, Eitan A., Scheinin, Mika, Wood, Alastair J. J., Ely, E. Wesley, Tyndale, Rachel F., Choi, Leena, Stein, C. Michael, Kurnik, Daniel
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.06.2012; Springer; Springer Nature B.V
• Subjects: Alleles; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Bayes Theorem; Bayesian analysis; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cytochrome P-450 CYP2A6; Cytochrome P450; Dexmedetomidine - blood; Dexmedetomidine - pharmacokinetics; Disposition; Drugs; Female; Genetic diversity; Genetic Variation; Genotype; Genotype & phenotype; Genotypes; Humans; Hypnotics and Sedatives - blood; Hypnotics and Sedatives - pharmacokinetics; Intensive care; Intensive Care Units; Male; Mathematical models; Medical sciences; Metabolism; Middle Aged; Pharmacogenetics; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; CYP2A6; Pharmacogenetics; Bayesian modeling; Dexmedetomidine; α2-Adrenergic receptor; Human; Agonist; Statistical analysis; Genetic variability; Enzyme; Cytochrome P450; Genotype; Modeling; Genetics; α-Adrenergic receptor agonist; Pharmacokinetics; Polymorphism
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-011-1208-z

Purpose 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. Conclusion Genetic variation in CYP2A6 does not appear to be an important determinant of dexmedetomidine clearance in ICU patients.