Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Clin Pharmacol Ther. 2012 Apr;91(4):692-9. doi: 10.1038/clpt.2011.280. Epub 2012 Mar 7.
Substantial variation exists in response to standard doses of codeine ranging from poor analgesia to life-threatening central nervous system (CNS) depression. We aimed to discover the genetic markers predictive of codeine toxicity by evaluating the associations between polymorphisms in cytochrome P450 2D6 (CYP2D6), UDP-glucuronosyltransferase 2B7 (UGT2B7), P-glycoprotein (ABCB1), mu-opioid receptor (OPRM1), and catechol O-methyltransferase (COMT) genes, which are involved in the codeine pathway, and the symptoms of CNS depression in 111 breastfeeding mothers using codeine and their infants. A genetic model combining the maternal risk genotypes in CYP2D6 and ABCB1 was significantly associated with the adverse outcomes in infants (odds ratio (OR) 2.68; 95% confidence interval (CI) 1.61-4.48; P(trend) = 0.0002) and their mothers (OR 2.74; 95% CI 1.55-4.84; P(trend) = 0.0005). A novel combination of the genetic and clinical factors predicted 87% of the infant and maternal CNS depression cases with a sensitivity of 80% and a specificity of 87%. Genetic markers can be used to improve the outcome of codeine therapy and are also probably important for other opioids sharing common biotransformation pathways.
在对标准剂量的可待因的反应中存在很大的差异，从镇痛效果不佳到危及生命的中枢神经系统 (CNS) 抑制。我们旨在通过评估细胞色素 P450 2D6 (CYP2D6)、UDP-葡萄糖醛酸转移酶 2B7 (UGT2B7)、P-糖蛋白 (ABCB1)、μ-阿片受体 (OPRM1) 和儿茶酚-O-甲基转移酶 (COMT) 基因多态性与中枢神经系统抑制症状之间的关联，这些基因与可待因途径有关，在 111 名使用可待因母乳喂养的母亲及其婴儿中发现可待因毒性的遗传标志物。一个结合了 CYP2D6 和 ABCB1 母体风险基因型的遗传模型与婴儿（比值比 (OR) 2.68；95%置信区间 (CI) 1.61-4.48；P(trend) = 0.0002）和母亲（OR 2.74；95% CI 1.55-4.84；P(trend) = 0.0005）的不良结局显著相关。遗传和临床因素的新组合预测了 87%的婴儿和母亲的中枢神经系统抑制病例，其敏感性为 80%，特异性为 87%。遗传标志物可用于改善可待因治疗的结果，对于具有共同生物转化途径的其他阿片类药物也可能很重要。
