Lisbeth Patteet, Vincent Haufroid, Kristof Maudens, Bernard Sabbe, Manuel Morrens, Hugo Neels
Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
Louvain Centre for Toxicology and Applied Pharmacology, Institute de recherche expérimentale et clinique, Université catholique de Louvain, Avenue E. Mounier 53, B-1200, Brussels, Belgium.
Eur J Clin Pharmacol. 2016 Feb;72(2):175-84. doi: 10.1007/s00228-015-1965-1. Epub 2015 Oct 30.
Therapeutic drug monitoring (TDM) of antipsychotics can aid in therapy optimization, explaining adverse effects or non-response. One reason for therapeutic failure or adverse effects is caused by genetic variations in the cytochrome P450 drug-metabolizing genes. The aim of this study was to evaluate the impact of CYP2D6 polymorphisms on steady-state serum concentrations of antipsychotics metabolized by CYP2D6, taking into account the co-medication with CYP2D6 inhibitors.
Serum and EDTA samples were collected from 82 psychiatric patients. After a liquid-liquid extraction, serum samples were analyzed using an ultra-high performance liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) method for quantification of the antipsychotics. CYP2D6 genotyping was performed using the Luminex xTAG® CYP2D6 Kit v3 (Luminex Corporation). Patients were divided into five phenotype subgroups by calculation of the activity score (AS): poor metabolizers (PM; AS 0), intermediate metabolizers (IM; AS 0.5-1), extensive metabolizers with slow activity (EM-s; AS 1-1.5), extensive metabolizers with fast activity (EM-f; AS 2), and ultra-rapid metabolizers (UM; AS >2). The influence of the phenotypes on the concentration-to-dose and metabolite-to-parent ratios was evaluated.
Overall, 6.1 % UM (n = 5), 25.6 % EM-f (n = 21), 46.3 % EM-s (n = 38), 1.2 % EM-s/EM-f (n = 1), 6.1 % IM (n = 5), and 14.6 % PM (n = 12) were found, taking co-administration of strong and moderate CYP2D6 inhibitors into account (phenoconversion). It was demonstrated that CYP2D6 polymorphisms affect the serum concentrations of aripiprazole (n = 18), haloperidol (n = 11), risperidone (n = 20), and zuclopenthixol (n = 6), while no influence was seen on the paliperidone serum concentrations (n = 31).
Even with a small number of patients per antipsychotic, the importance of CYP2D6 genotyping was still clearly stated. This study illustrates the high potential of combining TDM and CYP2D6 genotyping in clinical practice.
抗精神病药物的治疗药物监测（TDM）有助于优化治疗，解释不良反应或无反应情况。治疗失败或出现不良反应的一个原因是细胞色素P450药物代谢基因的遗传变异。本研究的目的是评估CYP2D6基因多态性对经CYP2D6代谢的抗精神病药物稳态血清浓度的影响，并考虑与CYP2D6抑制剂的联合用药情况。
收集了82名精神科患者的血清和乙二胺四乙酸（EDTA）样本。经过液-液萃取后，使用超高效液相色谱-串联质谱（UHPLC-MS/MS）法分析血清样本，以定量抗精神病药物。使用Luminex xTAG® CYP2D6试剂盒v3（Luminex公司）进行CYP2D6基因分型。通过计算活性评分（AS）将患者分为五个表型亚组：代谢缓慢者（PM；AS 0）、中间代谢者（IM；AS 0.5 - 1）、活性缓慢的广泛代谢者（EM-s；AS 1 - 1.5）、活性快速的广泛代谢者（EM-f；AS 2）和超快代谢者（UM；AS >2）。评估了这些表型对浓度-剂量比和代谢物-母体比的影响。
总体而言，考虑到强效和中度CYP2D6抑制剂的联合使用（表型转换），发现6.1%为UM（n = 5），25.6%为EM-f（n = 21），46.3%为EM-s（n = 38），1.2%为EM-s/EM-f（n = 1），6.1%为IM（n = 5），14.6%为PM（n = 12）。结果表明，CYP2D6基因多态性会影响阿立哌唑（n = 18）、氟哌啶醇（n = 11）、利培酮（n = 20）和珠氯噻醇（n = 6）的血清浓度，而对帕利哌酮血清浓度（n = 31）没有影响。
即使每种抗精神病药物的患者数量较少，CYP2D6基因分型的重要性仍清晰显现。本研究说明了在临床实践中将TDM与CYP2D6基因分型相结合的巨大潜力。
