Koller Dora, Saiz-Rodríguez Miriam, Zubiaur Pablo, Ochoa Dolores, Almenara Susana, Román Manuel, Romero-Palacián Daniel, de Miguel-Cáceres Alejandro, Martín Samuel, Navares-Gómez Marcos, Mejía Gina, Wojnicz Aneta, Abad-Santos Francisco
Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Pharmacology Department, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain.
Plataforma SCReN (Spanish Clinical Research Network), Instituto de Investigación Sanitaria La Princesa, UICEC Hospital Universitario de La Princesa, Madrid, Spain.
Br J Clin Pharmacol. 2020 Oct;86(10):2051-2062. doi: 10.1111/bcp.14300. Epub 2020 Apr 27.
Pupillography is a noninvasive and cost-effective method to determine autonomic nerve activity. Genetic variants in cytochrome P450 (CYP), dopamine receptor (DRD2, DRD3), serotonin receptor (HTR2A, HTR2C) and ATP-binding cassette subfamily B (ABCB1) genes, among others, were previously associated with the pharmacokinetics and pharmacodynamics of antipsychotic drugs. Our aim was to evaluate the effects of aripiprazole and olanzapine on pupillary light reflex related to pharmacogenetics.
Twenty-four healthy volunteers receiving 5 oral doses of 10 mg aripiprazole and 5 mg olanzapine tablets were genotyped for 46 polymorphisms by quantitative polymerase chain reaction. Pupil examination was performed by automated pupillometry. Aripiprazole, dehydro-aripiprazole and olanzapine plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry.
Aripiprazole affected pupil contraction: it caused dilatation after the administration of the first dose, then caused constriction after each dosing. It induced changes in all pupillometric parameters (P < .05). Olanzapine only altered minimum pupil size (P = .046). Polymorphisms in CYP3A, HTR2A, UGT1A1, DRD2 and ABCB1 affected pupil size, the time of onset of constriction, pupil recovery and constriction velocity. Aripiprazole, dehydro-aripiprazole and olanzapine pharmacokinetics were significantly affected by polymorphisms in CYP2D6, CYP3A, CYP1A2, ABCB1 and UGT1A1 genes.
In conclusion, aripiprazole and its main metabolite, dehydro-aripiprazole altered pupil contraction, but olanzapine did not have such an effect. Many polymorphisms may influence pupillometric parameters and several polymorphisms had an effect on aripiprazole, dehydro-aripiprazole and olanzapine pharmacokinetics. Pupillography could be a useful tool for the determination of autonomic nerve activity during antipsychotic treatment.
瞳孔描记术是一种用于测定自主神经活动的非侵入性且经济高效的方法。细胞色素P450（CYP）、多巴胺受体（DRD2、DRD3）、5-羟色胺受体（HTR2A、HTR2C）以及ATP结合盒亚家族B（ABCB1）等基因的遗传变异先前已与抗精神病药物的药代动力学和药效学相关联。我们的目的是评估阿立哌唑和奥氮平与药物遗传学相关的对瞳孔光反射的影响。
对24名接受5次口服10毫克阿立哌唑和5毫克奥氮平片剂量的健康志愿者，通过定量聚合酶链反应对46种多态性进行基因分型。通过自动瞳孔测量法进行瞳孔检查。采用高效液相色谱 - 串联质谱法测定阿立哌唑、脱氢阿立哌唑和奥氮平的血浆浓度。
阿立哌唑影响瞳孔收缩：给药第一剂后导致瞳孔扩张，随后每次给药后导致瞳孔收缩。它引起所有瞳孔测量参数的变化（P < 0.05）。奥氮平仅改变最小瞳孔大小（P = 0.046）。CYP3A、HTR2A、UGT1A1、DRD2和ABCB1中的多态性影响瞳孔大小、收缩开始时间、瞳孔恢复和收缩速度。阿立哌唑、脱氢阿立哌唑和奥氮平的药代动力学受到CYP2D6、CYP3A、CYP1A2、ABCB1和UGT1A1基因多态性的显著影响。
总之，阿立哌唑及其主要代谢物脱氢阿立哌唑改变了瞳孔收缩，但奥氮平没有这种作用。许多多态性可能影响瞳孔测量参数，并且几种多态性对阿立哌唑、脱氢阿立哌唑和奥氮平的药代动力学有影响。瞳孔描记术可能是抗精神病治疗期间测定自主神经活动的有用工具。
