Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Phayathai Rd, Pathumwan, Bangkok, 10330, Thailand.
Division of Neurology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Eur J Clin Pharmacol. 2022 Aug;78(8):1249-1259. doi: 10.1007/s00228-022-03322-1. Epub 2022 May 28.
This study aimed to evaluate the influence of genetic polymorphisms of drug-metabolizing enzyme genes, transporter gene, pathological gene (APOE), and non-genetic factors on therapeutic outcomes as well as steady-state plasma concentrations (Cpss) of galantamine in Thai patients with mixed dementia.
Fifty-one Thai patients with mixed dementia who received galantamine for at least 6 months were recruited. CYP2D6, CYP3A5, and ABCB1 polymorphisms were detected by TaqMan Genotyping Assay. UGT1A1 and APOE polymorphism was detected by direct Sanger sequencing technique and restriction fragment length polymorphism technique. Cpss of galantamine was measured by ultra-performance liquid chromatography. Associations of genetic and non-genetic factors with Cpss and clinical outcomes (change in cognitive function as measured by the Thai Mental State Examination (ΔTMSE) scores) were determined by using univariate and multivariate analysis.
The multivariate regression model revealed that patients who carried one or more detrimental allelic variant (CYP2D6, CYP3A5, and UGT1A1) showed a tendency toward a higher galantamine adjusted Cpss (B = 34.559, 95% CI = 0.741-68.377, p value = 0.045). Logistic regression analysis also revealed CYP2D6*10 carriers were significantly associated with higher ΔTMSE (B = 5.227, 95% CI = 2.395-8.060, p value = 0.001). UGT1A1 mutant alleles and non-genetic factors including concomitant use of statin drugs and higher education level can attenuate therapeutic outcomes of galantamine.
Pharmacokinetic-related genes including CYP2D6*10 and UGT1A1 mutant alleles were significantly associated with galantamine adjusted Cpss and cognitive function. Determination of Cpss and genotype could be an adjunct examination to provide further explanation in interindividual variability of galantamine therapeutic outcome.
本研究旨在评估药物代谢酶基因、转运体基因、病理基因（APOE）的遗传多态性以及非遗传因素对泰国混合性痴呆患者接受加兰他敏治疗的疗效和稳态血浆浓度（Css）的影响。
招募了 51 名接受加兰他敏治疗至少 6 个月的泰国混合性痴呆患者。采用 TaqMan 基因分型检测 CYP2D6、CYP3A5 和 ABCB1 多态性，采用直接 Sanger 测序技术和限制性片段长度多态性技术检测 UGT1A1 和 APOE 多态性。采用超高效液相色谱法测定加兰他敏的 Css。采用单变量和多变量分析确定遗传和非遗传因素与 Css 和临床结局（用泰国精神状态检查（TMSE）评分变化来衡量）的关系。
多变量回归模型显示，携带一个或多个有害等位变异（CYP2D6、CYP3A5 和 UGT1A1）的患者加兰他敏调整后的 Css 有升高趋势（B=34.559，95%CI=0.741-68.377，p 值=0.045）。Logistic 回归分析还显示，CYP2D6*10 携带者与更高的 TMSE 评分显著相关（B=5.227，95%CI=2.395-8.060，p 值=0.001）。UGT1A1 突变等位基因和非遗传因素（包括同时使用他汀类药物和较高的教育水平）可降低加兰他敏的疗效。
包括 CYP2D6*10 和 UGT1A1 突变等位基因在内的药代动力学相关基因与加兰他敏调整后的 Css 和认知功能显著相关。Css 和基因型的测定可以作为辅助检查，为加兰他敏治疗效果的个体间差异提供进一步的解释。
