CYP2A6 genetic variation and dexmedetomidine disposition

Utkarsh Kohli, Pratik Pandharipande, Mordechai Muszkat, Gbenga G. Sofowora, Eitan A. Friedman, Mika Scheinin, Alastair J.J. Wood, E. Wesley Ely, Rachel F. Tyndale, Leena Choi, C. Michael Stein, Daniel Kurnik*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

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 (n033), intermediate (n05), and slow metabolizers (n02). 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.

Original languageAmerican English
Pages (from-to)937-942
Number of pages6
JournalEuropean Journal of Clinical Pharmacology
Volume68
Issue number6
DOIs
StatePublished - Jun 2012
Externally publishedYes

Bibliographical note

Funding Information:
Funding This work was supported by Vanderbilt Clinical and Translational Science Award from the National Center for Research Resources [1 UL 1 RR024975]; National Institutes of Health grants [P01 HL56693, R21 AG034412, GM31304, and DA 020830]; and Center for Addiction and Mental Health and the Canadian Institutes for Health Research grant [MOP86471]. Dr. Pandharipande is supported via the Veterans Affairs Career Development Award, the American Society of Critical Care Anaesthesiologists-Foundation for Anaesthesia Education and Research Mentored Research Grant and the Vanderbilt Physician Scientists Development Award. Dr. Ely is supported by a Veterans Affairs Merit Award and National Institutes of Health grant [R01 AG027472-01A1]. Dr. Tyndale is a recipient of a Canada Research Chair in Pharmacogenetics. Dr. Choi is supported by National Institutes of Health grant [R21 AG034412]. Dr. Stein is the recipient of the Dan May Chair in Medicine.

Funding Information:
The laboratory of Dr. Scheinin has contract research relationships with Orion Corporation (Espoo, Finland) and Hospira (Lake Forest, IL, USA). Hospira has a license agreement with Orion Corporation concerning dexmedetomidine (Precedex®). Dr. Scheinin has received speaker fees and consulting fees from Orion Corporation, Dr. Pandhar-ipande has received research funding and honoraria from Hospira Inc., and Dr. Ely has received honoraria and grants from Hospira, Lilly, Pfizer, Glaxo Smith Kline, and Aspect Medical. None of the other authors has a conflict of interest relevant to the work presented.

Keywords

  • Bayesian modeling
  • CYP2A6
  • Dexmedetomidine
  • Pharmacogenetics

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