Department of Biological Systems, Metropolitan Autonomous University-Xochimilco, Mexico City, Mexico.
Master's Program in Pharmaceutical Sciences, Metropolitan Autonomous University-Xochimilco, Mexico City, Mexico.
Drug Dev Res. 2021 Aug;82(5):685-694. doi: 10.1002/ddr.21774. Epub 2020 Dec 17.
Clozapine (CLZ) is an atypical antipsychotic and the gold standard for refractory psychosis treatment. However, there is little information regarding pharmacogenetics of CLZ in patients with refractory psychosis and its clinical correlation with alcohol intake. Although neurological effects of CLZ in patients with concomitant alcohol intake are documented, its use is very common in patients with psychosis. We explored the impact of CYP1A2, CYP2D6, CYP2C19, and CYP3A4 genetic variants on CLZ pharmacokinetics and side effects, along with coffee/alcohol/tobacco consumption habits and clinical data of 48 adult patients with refractory psychosis on CLZ antipsychotic monotherapy. Relevant CYP variants in CLZ metabolism were evaluated by targeted genotyping and multiplex ligation-dependent probe amplification. CLZ and its main metabolite plasma concentrations were determined by high performance liquid chromatography. Biochemical and molecular data, along with other potential confounders, were included in the analysis by linear regression. Overall, CYP variants showed no effect on CLZ pharmacokinetics. The rs2069514 variant in homozygous genotype (also known as CYP1A2*1C/*1C) was associated with CLZ adverse reactions in Mexican patients with refractory psychosis (OR = 3.55 CI = 1.041-12.269, p = .043) and demonstrated that this effect is doubled by concomitant alcohol consumption (OR = 7.9 CI = 1.473-42.369, p = .016). Clinicians should be aware of this information before starting CLZ use, when treating patients with refractory psychosis, who are alcohol drinkers and carriers of this genetic variant in order to prevent CLZ-related adverse reactions. Nevertheless, our findings should be replicated in larger samples.
氯氮平（CLZ）是一种非典型抗精神病药，是治疗难治性精神病的金标准。然而，关于难治性精神病患者的 CLZ 药物遗传学及其与酒精摄入的临床相关性的信息很少。尽管有文献记载了同时摄入酒精对 CLZ 患者的神经影响，但它在精神病患者中非常常见。我们探讨了 CYP1A2、CYP2D6、CYP2C19 和 CYP3A4 遗传变异对 CLZ 药代动力学和副作用的影响，以及 48 名接受 CLZ 抗精神病单药治疗的难治性精神病成年患者的咖啡/酒精/吸烟习惯和临床数据。通过靶向基因分型和多重连接依赖性探针扩增评估 CLZ 代谢中的相关 CYP 变体。通过高效液相色谱法测定 CLZ 和其主要代谢物的血浆浓度。将生化和分子数据以及其他潜在的混杂因素纳入线性回归分析。总体而言，CYP 变体对 CLZ 药代动力学没有影响。在墨西哥难治性精神病患者中，纯合基因型（也称为 CYP1A2*1C/*1C）的 rs2069514 变体与 CLZ 不良反应相关（OR = 3.55，CI 95% = 1.041-12.269，p = 0.043），并且表明这种效应在同时饮酒时会增加一倍（OR = 7.9，CI 95% = 1.473-42.369，p = 0.016）。在开始使用 CLZ 治疗时，临床医生应在治疗同时饮酒且携带这种遗传变异的难治性精神病患者时了解这些信息，以防止与 CLZ 相关的不良反应。然而，我们的发现应该在更大的样本中得到复制。
