Zubiaur Pablo, Matas Miriam, Martín-Vílchez Samuel, Soria-Chacartegui Paula, Villapalos-García Gonzalo, Figueiredo-Tor Laura, Calleja Sofía, Navares-Gómez Marcos, de Miguel Alejandro, Novalbos Jesús, Mejía-Abril Gina, Luquero-Bueno Sergio, Román Manuel, Ochoa Dolores, Abad-Santos Francisco
Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP), 28006 Madrid, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28006 Madrid, Spain.
Pharmaceutics. 2022 Sep 21;14(10):2001. doi: 10.3390/pharmaceutics14102001.
Rasagiline is a selective and irreversible inhibitor of monoamine oxidase type B with neuroprotective effect, indicated for the management of Parkinson's disease. The aim of this work was to evaluate the impact of seven alleles and of 120 additional variants located in other CYP enzymes (e.g., ), UGT enzymes (e.g., ) or other enzymes (e.g., ), and transporters (e.g., ) on the pharmacokinetic variability and safety of rasagiline. A total of 118 healthy volunteers enrolled in four bioequivalence clinical trials consented to participate in this pharmacogenetic study. alleles were not associated with the pharmacokinetic variability of rasagiline. Patients with rs1045642 G/A+A/A genotypes presented higher area under the curve adjusted by dose per weight (AUC/DW) than those with the G/G genotype ( = 0.012) and lower volume of distribution (V/F) and clearance (Cl/F) ( = 0.001 and = 0.012, respectively). Subjects with the rs2273697 A/A genotype presented lower t (i.e., the time to reach the maximum concentration, C) compared to those with G/G+G/A genotypes ( = 0.001). Volunteers with the *1/*5 genotype exhibited lower C/DW and higher t ( = 0.003 and = 0.018, respectively) than subjects with the *1/*1 diplotype. Only one adverse drug reaction was reported: headache. Our results suggest the genetic polymorphism of drug transporters, rather than metabolizing enzymes, conditions the pharmacokinetics of rasagiline.
雷沙吉兰是一种具有神经保护作用的选择性、不可逆的单胺氧化酶B型抑制剂，用于帕金森病的治疗。本研究的目的是评估位于其他CYP酶（如......）、UGT酶（如......）或其他酶（如......）以及转运蛋白（如......）中的7个等位基因和120个其他变异对雷沙吉兰药代动力学变异性和安全性的影响。共有118名参加四项生物等效性临床试验的健康志愿者同意参与这项药物遗传学研究。[此处原文“ alleles”表述有误，推测为“某些等位基因”之类的意思，因信息不完整无法准确翻译]等位基因与雷沙吉兰的药代动力学变异性无关。rs1045642 G/A+A/A基因型的患者比G/G基因型的患者具有更高的按体重剂量调整的曲线下面积（AUC/DW）（P = 0.012），且分布容积（V/F）和清除率（Cl/F）更低（分别为P = 0.001和P = 0.012）。rs2273697 A/A基因型的受试者与G/G+G/A基因型的受试者相比，达到最大浓度（Cmax）的时间（tmax）更短（P = 0.001）。*1/5基因型的志愿者与1/*1双倍型的受试者相比，Cmax/DW更低，tmax更高（分别为P = 0.003和P = 0.018）。仅报告了一例药物不良反应：头痛。我们的结果表明，药物转运蛋白的基因多态性而非代谢酶决定了雷沙吉兰的药代动力学。
