Veiga M I, Asimus S, Ferreira P E, Martins J P, Cavaco I, Ribeiro V, Hai T N, Petzold M G, Björkman A, Ashton M, Gil J P
Malaria Research, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
Eur J Clin Pharmacol. 2009 Apr;65(4):355-63. doi: 10.1007/s00228-008-0573-8. Epub 2008 Nov 1.
The aim of this study was to obtain pharmacogenetic data in a Vietnamese population on genes coding for proteins involved in the elimination of drugs currently used for the treatment of malaria and human immunodeficiency virus/acquired immunodeficiency syndrome.
The main polymorphisms on the cytochrome P450 (CYP) genes, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP3A4 and CYP3A5, and the multi-drug resistance 1 gene (MDR1) were genotyped in 78 healthy Vietnamese subjects. Pharmacokinetic metrics were available for CYP2A6 (coumarin), CYP2C19 (mephenytoin), CYP2D6 (metoprolol) and CYP3As (midazolam), allowing correlations with the determined genotype.
In the CYP2 family, we detected alleles CYP2A6*4 (12%) and 5 (15%); CYP2B64 (8%), 6 (27%); CYP2C192 (31%) and 3 (6%); CYP2D64, *5, 10 (1, 8 and 44%, respectively). In the CYP3A family, CYP3A41B was detected at a low frequency (2%), whereas CYP3A5 *3 was detected at a frequency of 67%. The MDR1 3435T allele was present with a prevalence of 40%. Allele proportions in our cohort were compared with those reported for other Asian populations. CYP2C19 genotypes were associated to the S-4'-OH-mephenytoin/S-mephenytoin ratio quantified in plasma 4 h after intake of 100 mg mephenytoin. While CYP2D6 genotypes were partially reflected by the alpha-OH-metroprolol/metoprolol ratio in plasma 4 h after dosing, no correlation existed between midazolam plasma concentrations 4 h post-dose and CYP3A genotypes.
The Vietnamese subjects of our study cohort presented allele prevalences in drug-metabolising enzymes that were generally comparable with those reported in other Asian populations. Deviations were found for CYP2A64 compared to a Chinese population (12 vs. 5%, respectively; P = 0.023), CYP2A65 compared with a Korean population (15 vs. <1%, respectively; P < 0.0001), a Malaysian population (1%; P < 0.0001) and a Chinese population (1%; P < 0.0001); CYP2B6*6 compared with a Korean population (27 vs. 12%; P = 0.002) and a Japanese population (16%; P = 0.021). Pharmacokinetic metrics versus genotype analysis reinforces the view that the predictive value of certain globally common variants (e.g. CYP2D6 single nucleotide polymorphisms) should be evaluated in a population-specific manner.
本研究旨在获取越南人群中关于参与消除目前用于治疗疟疾和人类免疫缺陷病毒/获得性免疫缺陷综合征药物的蛋白质编码基因的药物遗传学数据。
对78名健康越南受试者的细胞色素P450（CYP）基因CYP2A6、CYP2B6、CYP2C19、CYP2D6、CYP3A4和CYP3A5以及多药耐药1基因（MDR1）的主要多态性进行基因分型。有CYP2A6（香豆素）、CYP2C19（美芬妥英）、CYP2D6（美托洛尔）和CYP3A（咪达唑仑）的药代动力学指标，可用于与所确定的基因型进行相关性分析。
在CYP2家族中，我们检测到等位基因CYP2A64（12%）和5（15%）；CYP2B64（8%）、6（27%）；CYP2C192（31%）和3（6%）；CYP2D6*4、5、10（分别为1%、8%和44%）。在CYP3A家族中，CYP3A41B的检测频率较低（2%），而CYP3A53的检测频率为67%。MDR1 3435T等位基因的流行率为40%。将我们队列中的等位基因比例与其他亚洲人群报告的比例进行了比较。CYP2C19基因型与摄入100 mg美芬妥英4小时后血浆中定量的S-4'-羟基美芬妥英/S-美芬妥英比值相关。虽然CYP2D6基因型在给药后4小时血浆中的α-羟基美托洛尔/美托洛尔比值中得到部分反映，但给药后4小时咪达唑仑血浆浓度与CYP3A基因型之间不存在相关性。
我们研究队列中的越南受试者在药物代谢酶中的等位基因流行率总体上与其他亚洲人群报告的相当。与中国人群相比，CYP2A64存在差异（分别为12%对5%；P = 0.023），与韩国人群相比，CYP2A65存在差异（分别为15%对<1%；P < 0.0001），与马来西亚人群相比（1%；P < 0.0001）以及与中国人群相比（1%；P < 0.0001）；与韩国人群相比，CYP2B6*6存在差异（27%对12%；P = 0.002）以及与日本人群相比（16%；P = 0.021）。药代动力学指标与基因型分析强化了这样一种观点，即某些全球常见变异（如CYP2D6单核苷酸多态性）的预测价值应以人群特异性方式进行评估。
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