Division of Biostatistics/Clinical Pharmacology, Indiana University, School of Medicine, 410 W. 10th St., HITS 3000, Indianapolis, IN 46202; e-mail:
J Clin Pharmacol. 2010 Apr;50(4):450-8. doi: 10.1177/0091270009359182. Epub 2010 Jan 15.
Accurate assessment of CYP2D6 phenotypes from genotype is inadequate in patients taking CYP2D6 substrate together with CYP2D6 inhibitors. A novel CYP2D6 scoring system is proposed that incorporates the impact of concomitant medications with the genotype in calculating the CYP2D6 activity score. Training (n = 159) and validation (n = 81) data sets were obtained from a prospective cohort tamoxifen pharmacogenetics registry. Two inhibitor factors were defined: 1 genotype independent and 1 genotype based. Three CYP2D6 gene scoring systems, and their combination with the inhibitor factors, were compared. These 3 scores were based on Zineh, Zanger, and Gaedigk's approaches. Endoxifen/NDM-Tam plasma ratio was used as the phenotype. The overall performance of the 3 gene scoring systems without consideration of CYP2D6-inhibiting medications in predicting CYP2D6 phenotype was poor in both the training set (R(2) = 0.24, 0.22, and 0.18) and the validation set (R(2) = 0.30, 0.24, and 0.15). Once the CYP2D6 genotype-independent inhibitor factor was integrated into the score calculation, the R(2) values in the training and validation data sets were nearly twice as high as the genotype-only scoring model: (0.44, 0.43, 0.38) and (0.53, 0.50, 0.41), respectively. The integration of the inhibitory effect of concomitant medications with the CYP2D6 genotype into the composite CYP2D6 activity score doubled the ability to predict the CYP2D6 phenotype. However, endoxifen phenotypes still varied substantially, even with incorporation of CYD2D6 genotype and inhibiting factors, suggesting that other, as yet unidentified factors must be involved in tamoxifen activation.
在同时服用 CYP2D6 底物和 CYP2D6 抑制剂的患者中，仅根据基因型评估 CYP2D6 表型并不准确。本研究提出了一种新的 CYP2D6 评分系统，该系统将伴随药物的影响与基因型相结合，用于计算 CYP2D6 活性评分。从前瞻性他莫昔芬药物遗传学登记处获得训练 (n=159) 和验证 (n=81) 数据集。定义了 2 个抑制剂因素：1 个基因型独立因素和 1 个基于基因型的因素。比较了 3 种 CYP2D6 基因评分系统及其与抑制剂因素的组合。这 3 个评分系统基于 Zineh、Zanger 和 Gaedigk 的方法。以依西美坦/NDM-他莫昔芬血浆比值作为表型。在不考虑 CYP2D6 抑制性药物的情况下，这 3 种基因评分系统在预测 CYP2D6 表型方面的整体表现均不佳，在训练集 (R(2)=0.24、0.22 和 0.18) 和验证集 (R(2)=0.30、0.24 和 0.15) 中均如此。一旦将 CYP2D6 基因型独立的抑制剂因素纳入评分计算中，训练和验证数据集的 R(2)值几乎是仅基于基因型评分模型的两倍：(0.44、0.43、0.38) 和 (0.53、0.50、0.41)。将伴随药物的抑制作用与 CYP2D6 基因型整合到复合 CYP2D6 活性评分中，提高了预测 CYP2D6 表型的能力。然而，即使纳入了 CYP2D6 基因型和抑制因素，依西美坦表型仍存在很大差异，这表明在他莫昔芬激活中还涉及其他尚未确定的因素。
