Department of Pharmacology, Faculty of Medicine of Monastir, University of Monastir, Avicenna Street, Monastir, 5019, Tunisia.
Department of Psychiatry, University Hospital of Monastir (Fattouma Bourguiba), Farhat Hached Street, Monastir, 5019, Tunisia.
Pharmacogenomics J. 2021 Oct;21(5):551-558. doi: 10.1038/s41397-021-00231-x. Epub 2021 Mar 17.
Clozapine (Clz) is an atypical antipsychotic, which its pharmacokinetics can be influenced by several factors. The CYP1A2 and CYP2C19, major enzymes implicated in Clz metabolism, present an interethnic variation on their activity caused by single nucleotide polymorphisms (SNPs). The present study investigated the influence of genetic and nongenetic factors on Clz pharmacokinetics in a southern Mediterranean population. We included adult Tunisian schizophrenic patients having received Clz and undergone a therapeutic drug monitoring (TDM) of Clz by morning C0 monitoring. The genomic DNA was extracted using a salting-out procedure. CYP1A21F (rs762551;-163C>A), CYP1A21C (rs2069514;-3860 G>A) and CYP 2C192 (rs4244285; 681G>A) was analyzed using PCR-RFLP. Fifty-one patients were enrolled in the study. The mutant allele (CYP1A21F) was the most frequently detected (58.8%). For CYP1A2*1F, Clz dose-normalized (C0/D ratio) was as high as 1.28 ± 0.37 in CC versus 0.67 ± 0.32 ng mL per mg day in AA group (p < 0.001). The influence of genetic (CYP1A2*1F, CYP1A2*1C and CYP2C19*2) and nongenetic parameters (age, weight, gender, tobacco, coffee, and alcohol consumption) on the variation of the Clz C0/D ratio was investigated. Only the CYP1A2*1 F polymorphism correlates significantly with the Clz C0/D variation and could explain 24% of its variability. Our data support a critical role of the CYP1A2 -163C>A on the variation of Clz exposure in Tunisian schizophrenic patients. Considering its narrow therapeutic range, CYP1A2 genotyping combined with TDM of Clz may improve efficacy and safety of this drug. Further studies are needed to investigate this issue.
氯氮平（Clz）是一种非典型抗精神病药，其药代动力学可受到多种因素的影响。CYP1A2 和 CYP2C19 是 Clz 代谢中的主要酶，其活性因单核苷酸多态性（SNP）而存在种族间差异。本研究调查了遗传和非遗传因素对南地中海人群中 Clz 药代动力学的影响。我们纳入了接受 Clz 治疗并进行清晨 C0 监测的成年突尼斯精神分裂症患者。使用盐析法提取基因组 DNA。使用 PCR-RFLP 分析 CYP1A21F(rs762551;-163C>A)、CYP1A21C(rs2069514;-3860G>A)和 CYP2C192(rs4244285;681G>A)。研究纳入了 51 例患者。突变等位基因（CYP1A21F）的检出率最高（58.8%）。对于 CYP1A2*1F，C0/D 比值的 Clz 剂量归一化（C0/D 比值）在 CC 组高达 1.28±0.37，而在 AA 组为 0.67±0.32ng·mL-1·mg-1·day-1（p<0.001）。研究了遗传（CYP1A2*1F、CYP1A2*1C 和 CYP2C19*2）和非遗传参数（年龄、体重、性别、吸烟、咖啡和饮酒）对 Clz C0/D 比值变化的影响。只有 CYP1A2*1F 多态性与 Clz C0/D 变异显著相关，可解释其变异性的 24%。我们的数据支持 CYP1A2-163C>A 对突尼斯精神分裂症患者 Clz 暴露变异的关键作用。考虑到其治疗窗较窄，CYP1A2 基因分型结合 Clz 的 TDM 可能会提高该药的疗效和安全性。需要进一步的研究来探讨这个问题。
