CYP2A6 genetic variation and dexmedetomidine disposition

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 (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.

Figure 1. Posterior medians of subject-specific clearance of dexmedetomidine according to genotype in intensive care patients

Each dot represents one patient. The darker the dots, the larger the number of samples per patient: the points with white color represent 1–2 samples/patient and black ones 15 samples/patient (see inbox legend). For intermediate and slow metabolizers, the number of samples is also presented. For normal metabolizers, the median number of samples was 5 (range, 1 to 15) per patient. Horizontal bars represent medians for subject-specific clearances in each metabolizer group.