Journal
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY
Volume 68, Issue 6, Pages 937-942Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00228-011-1208-z
Keywords
CYP2A6; Dexmedetomidine; Pharmacogenetics; Bayesian modeling
Categories
Funding
- Orion Corporation
- Hospira Inc.
- Hospira
- Lilly
- Pfizer
- Glaxo Smith Kline
- Aspect Medical
- National Center for Research Resources [1 UL 1 RR024975]
- National Institutes of Health [P01 HL56693, R21 AG034412, GM31304, DA 020830, R01 AG027472-01A1]
- Center for Addiction and Mental Health and the Canadian Institutes for Health Research [MOP86471]
- Veterans Affairs Career Development Award
- American Society of Critical Care Anaesthesiologists-Foundation for Anaesthesia Education and Research
- Vanderbilt Physician Scientists Development Award
- Veterans Affairs Merit Award
- Canada Research Chair in Pharmacogenetics
- Dan May Chair in Medicine
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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 affects the clearance of other substrate drugs. We examined whether genotypes affect dexmedetomidine disposition. 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 alleles and grouped into normal ( = 33), intermediate ( = 5), and slow metabolizers ( = 2). 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 metabolizer groups. Genetic variation in does not appear to be an important determinant of dexmedetomidine clearance in ICU patients.
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