Somogyi Andrew A, Barratt Daniel T, Coller Janet K
Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, Australia.
Clin Pharmacol Ther. 2007 Mar;81(3):429-44. doi: 10.1038/sj.clpt.6100095.
Opioids are used for acute and chronic pain and dependency. They have a narrow therapeutic index and large interpatient variability in response. Genetic factors regulating their pharmacokinetics (metabolizing enzymes, transporters) and pharmacodynamics (receptors and signal transduction elements) are contributors to such variability. The polymorphic CYP2D6 regulates the O-demethylation of codeine and other weak opioids to more potent metabolites with poor metabolizers having reduced antinociception in some cases. Some opioids are P-glycoprotein substrates, whereas, ABCB1 genotypes inconsistently influence opioid pharmacodynamics and dosage requirements. Single-nucleotide polymorphisms in the mu opioid receptor gene are associated with increasing morphine, but not methadone dosage requirements and altered efficacy of mu opioid agonists and antagonists. As knowledge regarding the interplay between genes affecting opioid pharmacokinetics including cerebral kinetics and pharmacodynamics increases, our understanding of the role of pharmacogenomics in mediating interpatient variability in efficacy and side effects to this important class of drugs will be better informed. Opioid drugs as a group have withstood the test of time in their ability to attenuate acute and chronic pain. Since the isolation of morphine in the early 1800s by Friedrich Sertürner, a large number of opioid drugs beginning with modification of the 4,5-epoxymorphinan ring structure were developed in order to improve their therapeutic margin, including reducing dependence and tolerance, ultimately without success.
阿片类药物用于治疗急慢性疼痛及成瘾。它们的治疗指数狭窄，患者间反应差异大。调节其药代动力学（代谢酶、转运体）和药效动力学（受体及信号转导元件）的遗传因素是造成这种差异的原因。多态性CYP2D6调节可待因及其他弱阿片类药物的O-去甲基化，生成更强效的代谢产物，在某些情况下，代谢不良者的抗伤害感受作用会减弱。一些阿片类药物是P-糖蛋白底物，而ABCB1基因型对阿片类药物药效动力学和剂量需求的影响并不一致。μ阿片受体基因中的单核苷酸多态性与吗啡剂量增加有关，但与美沙酮剂量需求及μ阿片激动剂和拮抗剂疗效改变无关。随着对影响阿片类药物药代动力学（包括脑动力学）和药效动力学的基因间相互作用的认识不断增加，我们对药物基因组学在介导这类重要药物患者间疗效和副作用差异中所起作用的理解将更加深入。作为一个药物类别，阿片类药物在减轻急慢性疼痛方面经受住了时间的考验。自19世纪初弗里德里希·塞尔图纳分离出吗啡以来，人们开发了大量以修饰4,5-环氧吗啡喃环结构为开端的阿片类药物，以提高其治疗窗，包括减少依赖性和耐受性，但最终均未成功。
