Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers
Allele-specific change of concentration and functional gene dose for the prediction of steady-state serum concentrations of amitriptyline and nortriptyline in CYP2C19 and CYP2D6 extensive and intermediate metabolizers
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DOI：
10.1373/clinchem.2003.030825
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发表时间：
2004-09-01
影响因子：
9.3
通讯作者：
Leucht, S
中科院分区：
文献类型：
--
作者：
Steimer, W;Zöpf, K;Leucht, S
背景最近，新的多态性被描述与中间和超速CYP 2D 6代谢。这些可以允许对快代谢者组内的代谢活性进行非常期望的预测。方法：我们进行了一项前瞻性、双盲、双中心研究，寻求CYP 2C 19与糖尿病患者的相关性。（*2、*3和 *4;常规PCR）和CYP 2D 6基因型50名接受阿米替林治疗的高加索人的药物浓度（*1至 *10、*35和 *41;实时和多重PCR）和药物浓度（Emit（R）和HPLC）结果：18例CYP 2C 19杂合子（*1/*2）与30例纯合子（*1/*1）相比，AT明显升高（P = 0.033），去甲替林（NT; P = 0.059）明显降低。对于CYP 2D 6，我们计算了两个新的指数，即，等位基因特异性相同背景浓度变化（ASCOC）和定量功能基因剂量。ASCOC描述了与野生型相比，突变等位基因引起的NT浓度变化。我们发现等位基因 *4（95.6%; P < 0.0001）、*10（63.3%; P < 0.001）和 *41（39.8%; P < 0.0001）的浓度显著更高，但 *2和 *35的浓度没有显著升高。对每个等位基因使用0、0.5或1的半定量基因剂量，而不是应用当前的分类系统（预测表型：3个中间代谢型，46个快速代谢型和1个超快速代谢型）产生显著的NT浓度差异：基因剂量为0.5（n =3）、1（n = 14）、1.5（n = 11）、2（n = 21）和3（n = 1; P < 0.00001）。与目前的分析方法相比，ASCOC提供了实质性的优势。CYP 2D 6而非CYP 2C 19与用于指导AT治疗的两种浓度之和相关。(C)2004年美国临床化学协会。
Background. Recently, new polymorphisms were described in connection with intermediate and ultrarapid CYP2D6 metabolism. These may allow a much desired prediction of metabolic activity within the extensive metabolizer group. The functional consequences are still being discussed with few data available for clinical patients.Methods: We conducted a prospective, blinded two-center study seeking correlations between CYP2C19 (*2,*3, and *4; conventional PCR) and CYP2D6 genotypes (*1 to *10, *35, and *41; real-time and multiplex PCR) and drug concentrations (Emit(R) and HPLC) in 50 Caucasians receiving amitriptyline (AT; 75 mg twice a day).Results: Eighteen CYP2C19 heterozygotes (*1/*2) had higher AT (P = 0.033) and lower nortriptyline (NT; P = 0.059) concentrations than 30 homozygotes (*1/*1). For CYP2D6, we calculated two new indices, i.e., the allele-specific change of concentration on identical background (ASCOC) and a quantitative functional gene dose. The ASCOC describes the change in NT concentration attributable to a mutant allele compared with the wild type. We found significantly higher concentrations for alleles *4 (95.6%; P < 0.0001), *10 (63.3%; P < 0.001), and *41 (39.8%; P < 0.0001) but not for *2 and *35. Assigning of semiquantitative gene doses of 0, 0.5, or 1 to each allele instead of applying the current classification system (predicted phenotypes: 3 intermediate metabolizers, 46 extensive metabolizers, and 1 ultrarapid metabolizer) produced significant NT concentration differences: gene doses of 0.5 (n =3), 1 (n = 14), 1.5 (n = 11), 2 (n = 21) and 3 (n = 1; P < 0.00001).Conclusions: AT and NT concentrations can be predicted within the group of CYP2D6 extensive metabolizers. The ASCOC provides substantial advantages compared with current methods of analysis. CYP2D6 but not CYP2C19 correlates with the sum of both concentrations used to guide AT therapy. (C) 2004 American Association for Clinical Chemistry.