Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.
Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, Thailand.
Sci Rep. 2021 Feb 18;11(1):4158. doi: 10.1038/s41598-021-83570-w.
Recently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) have revised recommendations for the translation of CYP2D6 genotype to phenotype. Changes affect phenotype grouping, as well as the value used to calculate activity score for the CYP2D610 allele to better reflect the substantially decreased activity of this allele which is the most frequent allele found in Asian populations. This study aimed to evaluate whether the lower value for CYP2D610 as recommended, and the revised phenotype groupings improve the relationship between CYP2D6 genotype and risperidone measures. One hundred and ninety-nine children and adolescents with autism treated with a risperidone-based regimen for at least four weeks were included. CYP2D6 genotype was determined using the Luminex xTAG CYP2D6 Kit assay and translated into phenotype using different translation methods. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using LC/MS/MS. Plasma levels of risperidone, risperidone concentration/dose ratio, and risperidone/9-hydroxyrisperidone ratio in patients with an activity score < 1 were significantly higher than those ≥ 1 (P value < 0.001 for all three parameters). Plasma risperidone levels and risperidone concentration/dose ratios were significantly higher in intermediate metabolizers (defined as AS = 0.25-0.75) than normal metabolizer (defined as AS = 1-2) patients (1.44 vs. 0.23 ng/ml, P < 0.001 and 1.63 vs. 0.29 ng/ml/ng, P < 0.001, respectively) as well as risperidone/9-hydroxyrisperidone ratio (0.20 vs. 0.04, P < 0.001). This is the first study in an Asian population utilizing the revised CPIC-recommended method for translating the CYP2D6 genotype to phenotype. In addition to validating that CYP2D6 genetic variation significantly impacts risperidone metabolism, we demonstrated that revised value for the CYP2D6*10 was superior for genotype to phenotype translation. However, at least for risperidone, subjects with an activity score of 1 presented as phenotypic normal, and not intermediate metabolizers, suggesting that phenotype classification is substrate dependent.
最近，临床药物遗传学实施联盟（CPIC）修订了 CYP2D6 基因型到表型的翻译建议。这些变化影响表型分组，以及用于计算 CYP2D610 等位基因活性评分的数值，以更好地反映该等位基因的活性显著降低，而该等位基因是亚洲人群中最常见的等位基因。本研究旨在评估 CPIC 推荐的 CYP2D610 较低值和修订的表型分组是否能改善 CYP2D6 基因型与利培酮测量之间的关系。本研究纳入了 199 名接受利培酮为基础的治疗方案至少四周的自闭症儿童和青少年。使用 Luminex xTAG CYP2D6 试剂盒测定 CYP2D6 基因型，并使用不同的翻译方法将其转化为表型。使用 LC/MS/MS 测定利培酮和 9-羟基利培酮的血浆浓度。活性评分<1 的患者的利培酮、利培酮浓度/剂量比和利培酮/9-羟基利培酮比值的血浆水平显著高于活性评分≥1 的患者（所有三个参数的 P 值均<0.001）。中代谢者（定义为 AS=0.25-0.75）的利培酮血浆水平和利培酮浓度/剂量比明显高于正常代谢者（定义为 AS=1-2）（1.44 与 0.23ng/ml，P<0.001 和 1.63 与 0.29ng/ml/ng，P<0.001），以及利培酮/9-羟基利培酮比值（0.20 与 0.04，P<0.001）。这是首次在亚洲人群中利用 CPIC 推荐的方法将 CYP2D6 基因型转化为表型的研究。除了验证 CYP2D6 遗传变异显著影响利培酮代谢外，我们还证明了 CYP2D6*10 的修订值更适合用于基因型到表型的翻译。然而，至少对于利培酮，活性评分 1 的患者表现为表型正常，而不是中间代谢者，这表明表型分类是底物依赖性的。
