Departments of Medicine and Pharmacology, Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, USA.
Eur J Clin Pharmacol. 2012 Jun;68(6):937-42. doi: 10.1007/s00228-011-1208-z. Epub 2012 Jan 21.
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.
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).
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.
Genetic variation in CYP2A6 does not appear to be an important determinant of dexmedetomidine clearance in ICU patients.
在重症监护病房（ICU）接受镇静治疗的患者中，右美托咪定的剂量需求存在较大的个体间差异。细胞色素 P450 2A6（CYP2A6）介导右美托咪定代谢的重要途径，CYP2A6 的遗传变异影响其他底物药物的清除率。我们研究了 CYP2A6 基因型是否影响右美托咪定的处置。
在 43 名接受右美托咪定输注以达到所需镇静水平的重症 ICU 患者中，我们每例患者均测定了中位数为 5 次的血浆右美托咪定浓度。40 名患者进行了 5 种常见 CYP2A6 等位基因的基因分型，并分为正常代谢者（n = 33）、中间代谢者（n = 5）和慢代谢者（n = 2）。
使用贝叶斯分层非线性混合模型，估计右美托咪定清除率为 49.1 L/h（后验均值；95%可信区间 41.4-57.6 L/h）。正常、中间和慢 CYP2A6 代谢者组之间右美托咪定清除率无显著差异。
CYP2A6 的遗传变异似乎不是 ICU 患者右美托咪定清除率的重要决定因素。
