Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication
Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication
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DOI：
10.1038/sj.tpj.6500406
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发表时间：
2007-08-01
影响因子：
2.8
通讯作者：
Brockmoeller, J.
中科院分区：
文献类型：
--
作者：
Kirchheiner, J.;Schmidt, H.;Brockmoeller, J.
可待因是一种主要通过其代谢物吗啡作用于Mu阿片受体的止痛药，吗啡几乎完全由遗传多态酶细胞色素P450 2D6(CYP2D6)形成。虽然已知缺乏CYP2D6活性的个体(代谢不良者，PM)对可待因的镇痛效果较差，但由于CYP2D6基因复制而产生的超快代谢者(UM)可能会经历夸大的甚至潜在危险的阿片能效应，迄今尚未对此问题进行系统的研究。将30毫克可待因单次注射给12微米携带有CYP2D6基因重复的底物、11种广泛代谢物(EM)和3种PM用聚合酶链式反应-限制性片段长度多态法进行基因分型，用单碱基引物延伸法分析基因重复等位基因。在服药后24 h内测定药物动力学，用高效液相色谱-串联质谱法分析血浆和尿液中的可待因及其代谢物。EM组和UM组吗啡血药浓度-时间曲线下面积差异有统计学意义(P=0.02)，EM组和UM组吗啡血药浓度-时间曲线下面积的中位数分别为11(5-17)mU/h L(-1)和16(10-24)mU/h L(-1)。在12h以上的尿液中，可待因+可待因-6-葡萄糖醛酸苷的代谢率分别为11(6~17)和9(6~16)(P=0.05)。11例患者中有10例(91%)感觉到镇静，而12例患者中有6例(50%)感到镇静(P=0.03)。与EM相比，预测超快代谢的CYP2D6基因导致吗啡及其葡萄糖醛酸苷的血浆浓度增加约50%。在我们的研究中，UMS中没有看到严重的不良反应，很可能是因为出于安全原因，我们使用了只有30毫克的低剂量。如果内科医生在使用可待因之前知道患者的CYP2D6重复基因，那将是一件好事。
Codeine is an analgesic drug acting on mu-opiate receptors predominantly via its metabolite morphine, which is formed almost exclusively by the genetically polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Whereas it is known that individuals lacking CYP2D6 activity (poor metabolizers, PM) suffer from poor analgesia from codeine, ultra- fast metabolizers (UM) due to the CYP2D6 gene duplication may experience exaggerated and even potentially dangerous opioidergic effects and no systematical study has been performed so far on this question. A single dose of 30 mg codeine was administered to 12 UM of CYP2D6 substrates carrying a CYP2D6 gene duplication, 11 extensive metabolizers (EM) and three PM. Genotyping was performed using polymerase chain reaction- restriction fragment length polymorphism methods and a single- base primer extension method for characterization of the gene- duplication alleles. Pharmacokinetics was measured over 24 h after drug intake and codeine and its metabolites in plasma and urine were analyzed by liquid chromatography with tandem mass spectrometry. Significant differences between the EM and UM groups were detected in areas under the plasma concentration versus time curves (AUCs) of morphine with a median (range) AUC of 11 (5 - 17) mu g h l(-1) in EMs and 16 (10-24) mu g h l(-1) in UM (P = 0.02). In urine collected over 12 h, the metabolic ratios of the codeine+codeine-6-glucuronide divided by the sum of morphine+its glucuronides metabolites were 11 (6-17) in EMs and 9 (6-16) in UM (P = 0.05). Ten of the 11 CYP2D6 UMs felt sedation (91%) compared to six (50%) of the 12 EMs (P = 0.03). CYP2D6 genotypes predicting ultrarapid metabolism resulted in about 50% higher plasma concentrations of morphine and its glucuronides compared with the EM. No severe adverse effects were seen in the UMs in our study most likely because we used for safety reasons a low dose of only 30 mg. It might be good if physicians would know about the CYP2D6 duplication genotype of their patients before administering codeine.