Can extremely low or high morphine formation from codeine be predicted prior to therapy initiation?
Can extremely low or high morphine formation from codeine be predicted prior to therapy initiation?
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DOI：
10.1016/j.pain.2009.03.023
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发表时间：
2009-07-01
期刊：
影响因子：
7.4
通讯作者：
Geisslinger, Gerd
中科院分区：
文献类型：
--
作者：
Loetsch, Joern;Rohrbacher, Maren;Geisslinger, Gerd
可待因通过O-去甲基化激活为吗啡是其镇痛作用和严重毒性的先决条件。识别吗啡形成量极低或极高的患者可能会提高可待因治疗的疗效和安全性。为了评估这种识别的可能性，我们比较了 57 名健康白种人口服 30 mg 氢溴酸右美沙芬或 50 mg 可待因后当前 CYP2D6 表型关联系统（传统的基于基因型的分类、最近提出的 CYP2D6 活性评分和血浆右美沙芬代谢比）的性能。大多数受试者 (87.5%) 从可待因形成吗啡的比例低于 15%，因此可能对可待因治疗没有反应，这些受试者被基于 CYP2D6 基因型 OF 表型的系统正确识别。相比之下，在吗啡形成量高于 15% 且有阿片类药物毒性风险的受试者中，CYP2D6 基因分型仅预测 50% 的受试者携带基因重复，而基于右美沙芬的表型分析则识别出 67.5% 的受试者具有高吗啡形成量。然而，只有将基因分型与表型分析相结合时，才能实现对高吗啡形成的令人满意的预测（87.5%）。总之，目前可以很好地预测可待因形成的吗啡不足，因此镇痛可能失败。然而，为了使可待因治疗安全，还必须预测极高的吗啡形成，这必须通过将基因分型与表型分析相结合来获得。 (C) 2009 年国际疼痛研究协会。由 Elsevier B.V. 出版。保留所有权利。
Activation of codeine by O-demethylation into morphine is a prerequisite for its analgesic effects and severe toxicity. Identifying patients in whom morphine is formed either at extremely low or at extremely high amounts may improve efficacy and safety of codeine therapy. To assess how well this identification is possible, we compared the performance of current CYP2D6 phenotype association systems (traditional genotype-based classification, a recently proposed CYP2D6 activity score, and the plasma dextromethorphan metabolic ratio) in 57 healthy Caucasians after oral administration of 30 mg dextromethorphan hydrobromide or 50 mg codeine. Most subjects (87.5%) at the lower 15% of morphine formation from codeine and thus likely to not to respond to codeine therapy were correctly identified by CYP2D6 genotype- OF phenotype-based systems. In contrast, in subjects at the Upper 15% of morphine formation being at risk for opioid toxicity, CYP2D6 genotyping predicted only the 50% who carried gene duplication, whereas dextromethorphan-based phenotyping identified 67.5% of the Subjects with high morphine formation. However, satisfactory prediction (87.5%) of high morphine formation was only achieved when combining genotyping with phenotyping. In Conclusion, insufficient morphine formation from codeine and thus likely failure of analgesia can Currently be well predicted. However, to make codeine therapy safe, extremely high morphine formation has to be predicted as well, which has to be obtained at the effort of combining genotyping with phenotyping. (C) 2009 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.