Wu Xiujun, Yuan Li, Zuo Jinliang, Lv Jing, Guo Tao
Eur J Clin Pharmacol. 2014 Jan;70(1):57-63. doi: 10.1007/s00228-013-1573-x.
Codeine is an analgesic drug acting on μ-opioid receptors predominantly via its metabolite morphine formed almost exclusively by CYP2D6. Genetic polymorphisms in CYP2D6 are associated with diminished pain relief and/or severe opioid side effects. In Chinese individuals, CYP2D6*10 is the most common allele with reduced enzyme activity. In this study, we investigated the effect of this allele on the pharmacokinetics of codeine and its metabolites.
A blood sample was collected from healthy Mongolian volunteers for CYP2D6 genotyping using a PCR-RFLP assay. A pharmacokinetic study was then carried out in three groups with CYP2D6*1/1 (n=10), CYP2D61/10 (n=10) and CYP2D610/*10 (n=9) genotypes by collecting serial blood samples for determination of plasma levels of codeine and its metabolites, morphine, morphine 3-glucuronide (M3G) and morphine 6-glucuronide (M6G) before and after a single 30-mg oral dose of codeine phosphate. Codeine and its metabolites were measured by LC-MS/MS.
No significant differences were observed in the pharmacokinetic parameters of codeine in the three genotype groups. However, the C( max) and AUC(0-∞) of morphine, M3G and M6G were significantly different between the study groups (P<0.05). Compared with the *1/*1 group, the AUC(0-∞) for morphine in the *1/*10 and *10/*10 groups decreased by ratios (95 % CI) of 0.93 (0.26-1.59) and 0.494 (0.135-0.853) respectively. Corresponding ratios for M3G were 0.791 (0.294-1.288) and 0.615 (0.412-0.818) and for M6G were 0.643 (0.39-0.957) and 0.423 (0.267-0.579).
This study demonstrates that the CYP2D6*10 allele plays an important role in the pharmacokinetics of the O-demethylated metabolites of codeine after oral administration.
可待因是一种镇痛药，主要通过其代谢产物吗啡作用于μ-阿片受体，而吗啡几乎完全由CYP2D6生成。CYP2D6基因多态性与疼痛缓解减弱和/或严重的阿片类药物副作用相关。在中国人群中，CYP2D6*10是酶活性降低的最常见等位基因。在本研究中，我们调查了该等位基因对可待因及其代谢产物药代动力学的影响。
采集健康蒙古族志愿者的血样，采用聚合酶链反应-限制性片段长度多态性分析（PCR-RFLP）进行CYP2D6基因分型。然后对CYP2D6*1/1（n = 10）、CYP2D61/10（n = 10）和CYP2D610/*10（n = 9）三种基因型的三组受试者进行药代动力学研究，单次口服30 mg磷酸可待因前后采集系列血样，测定血浆中可待因及其代谢产物吗啡、吗啡3-葡萄糖醛酸苷（M3G）和吗啡6-葡萄糖醛酸苷（M6G）的水平。采用液相色谱-串联质谱法（LC-MS/MS）测定可待因及其代谢产物。
三个基因型组可待因的药代动力学参数无显著差异。然而，研究组之间吗啡、M3G和M6G的Cmax和AUC(0-∞)有显著差异（P<0.05）。与*1/*1组相比，*1/10组和10/*10组中吗啡的AUC(0-∞)分别下降了0.93（0.26 - 1.59）和0.494（0.135 - 0.853）。M3G的相应下降比例分别为0.791（0.294 - 1.288）和0.615（0.412 - 0.818），M6G的相应下降比例分别为0.643（0.39 - 0.957）和0.423（0.267 - 0.579）。
本研究表明，CYP2D6*10等位基因在口服给药后可待因O-去甲基化代谢产物的药代动力学中起重要作用。
