Research Centre for Natural Sciences, Institute of Enzymology, Hungarian Academy of Sciences, Magyar Tudósok 2, Budapest, 1117, Hungary.
Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary.
Eur Arch Psychiatry Clin Neurosci. 2020 Feb;270(1):71-82. doi: 10.1007/s00406-018-0975-2. Epub 2019 Jan 2.
The efficacy of aripiprazole therapy and the risk of adverse reactions are influenced by substantial inter-individual variability in aripiprazole metabolizing capacity. In vitro studies assigned the potential role in aripiprazole metabolism to CYP2D6 and CYP3A enzymes; therefore, the association between the steady-state aripiprazole plasma concentrations and patients' CYP2D6 and CYP3A statuses (CYP2D6, CYP3A4, and CYP3A5 genotypes, and CYP3A4 expression) and/or co-medication with CYP function modifying medications has been investigated in 93 psychiatric patients on stable aripiprazole therapy. The patients' CYP2D6 genotype had a major effect on aripiprazole plasma concentrations, whereas contribution of CYP3A genotypes and CYP3A4 expression to aripiprazole clearance were considered to be minor or negligible. The role of CYP3A4 expression in aripiprazole metabolism did not predominate even in the patients with nonfunctional CYP2D6 alleles. Furthermore, dehydroaripiprazole exposure was also CYP2D6 genotype-dependent. Dehydroaripiprazole concentrations were comparable with aripiprazole levels in patients with functional CYP2D6 alleles, and 35% or 22% of aripiprazole concentrations in patients with one or two non-functional CYP2D6 alleles, respectively. The concomitant intake of CYP2D6 inhibitors, risperidone, metoprolol, or propranolol was found to increase aripiprazole concentrations in patients with at least one wild-type CYP2D6*1 allele. Risperidone and 9-hydroxy-risperidone inhibited both dehydrogenation and hydroxylation of aripiprazole, whereas metoprolol and propranolol blocked merely the formation of the active dehydroaripiprazole metabolite, switching towards the inactivation pathways. Patients' CYP2D6 genotype and co-medication with CYP2D6 inhibitors can be considered to be the major determinants of aripiprazole pharmacokinetics. Taking into account CYP2D6 genotype and co-medication with CYP2D6 inhibitors may improve the outcomes of aripiprazole therapy.
阿立哌唑治疗的疗效和不良反应风险受到其代谢能力的个体间差异的显著影响。体外研究将阿立哌唑代谢的潜在作用归因于 CYP2D6 和 CYP3A 酶；因此，在 93 名接受稳定阿立哌唑治疗的精神科患者中，研究了稳态阿立哌唑血浆浓度与患者 CYP2D6 和 CYP3A 状态（CYP2D6、CYP3A4 和 CYP3A5 基因型和 CYP3A4 表达）和/或与 CYP 功能修饰药物的共同给药之间的关系。患者的 CYP2D6 基因型对阿立哌唑的血浆浓度有主要影响，而 CYP3A 基因型和 CYP3A4 表达对阿立哌唑清除率的贡献被认为是次要或可忽略的。即使在无功能 CYP2D6 等位基因的患者中，CYP3A4 表达在阿立哌唑代谢中的作用也不占主导地位。此外，脱氢阿立哌唑的暴露也依赖于 CYP2D6 基因型。在具有功能性 CYP2D6 等位基因的患者中，脱氢阿立哌唑的浓度与阿立哌唑水平相当，而在具有一个或两个无功能 CYP2D6 等位基因的患者中，分别为阿立哌唑浓度的 35%或 22%。发现同时服用 CYP2D6 抑制剂利培酮、美托洛尔或普萘洛尔会增加至少一个野生型 CYP2D6*1 等位基因的患者的阿立哌唑浓度。利培酮和 9-羟基利培酮抑制阿立哌唑的脱氢和羟化作用，而美托洛尔和普萘洛尔仅阻断活性脱氢阿立哌唑代谢物的形成，转而走向失活途径。患者的 CYP2D6 基因型和与 CYP2D6 抑制剂的共同给药可被认为是阿立哌唑药代动力学的主要决定因素。考虑 CYP2D6 基因型和与 CYP2D6 抑制剂的共同给药可能会改善阿立哌唑治疗的结果。
