Ozdemir Fezile, Oz Merve Demirbugen, Tok Kenan Can, Dural Emrah, Kır Yagmur, Gumustas Mehmet, Baskak Bora, Suzen H Sinan
Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Final International University, AS128 Kyrenia, North Cyprus, Via Mersin 10, Turkey.
Faculty of Pharmacy, Department of Pharmaceutical Toxicology, Ankara University, Ankara, Turkey.
Toxicol Appl Pharmacol. 2025 Feb;495:117219. doi: 10.1016/j.taap.2024.117219. Epub 2025 Jan 4.
Clozapine (CLZ) is an antipsychotic which is particularly used in treatment resistant schizophrenia patients who do not respond to other agents. It is preferred because it reduces suicidal behaviours and attempts, reducing aggression and violent behaviour. The aim of the study is to evaluate the effects of ABCB1 rs1045642 and UGT1A4 rs2011425 polymorphisms on CLZ and its major metabolite N- desmethly clozapine (DCLZ) plasma concentrations in patients with schizophrenia. A total 109 of Turkish patients with schizophrenia on continually administered CLZ monotherapy were included. The plasma concentrations of CLZ and DCLZ were measured using an HPLC after liquid-liquid extraction while, transporter gene ABCB1 and phase two enzyme UGT1A4 polymorphisms were identified using PCR- RFLP method. Results showed that UGT1A4*3 polymorphism has statistically significant effects on CLZ C/D and DCLZ C/D levels in patients with sub/supra therapeutic levels while ABCB1 C3435T polymorphism has a significant effect on CLZ/DCLZ ratio among patients who have subtherapeutic levels. This study indicates the influence of genetic differences on plasma levels and highlights the importance of pharmacogenetic studies in clinic. Using the obtained results as pharmacogenetic biomarkers will help clinicians provide effective treatment in individual patients and reduce the undesirable side effects.
氯氮平（CLZ）是一种抗精神病药物，特别用于治疗对其他药物无反应的难治性精神分裂症患者。它之所以更受青睐，是因为它能减少自杀行为和企图，降低攻击性和暴力行为。本研究的目的是评估ABCB1 rs1045642和UGT1A4 rs2011425基因多态性对精神分裂症患者血浆中氯氮平及其主要代谢产物N-去甲基氯氮平（DCLZ）浓度的影响。总共纳入了109名持续接受氯氮平单一疗法治疗的土耳其精神分裂症患者。采用液-液萃取后用高效液相色谱法测定氯氮平和DCLZ的血浆浓度，同时采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法鉴定转运体基因ABCB1和二期酶UGT1A4的多态性。结果显示，UGT1A4*3基因多态性对处于亚/超治疗水平的患者的氯氮平C/D和DCLZ C/D水平有统计学显著影响，而ABCB1 C3435T基因多态性对处于亚治疗水平的患者的氯氮平/DCLZ比值有显著影响。本研究表明基因差异对血浆水平的影响，并强调了临床药物遗传学研究的重要性。将获得的结果用作药物遗传学生物标志物将有助于临床医生为个体患者提供有效的治疗，并减少不良副作用。
