González-Iglesias Eva, Méndez-Ponce Clara, Ochoa Dolores, Román Manuel, Mejía-Abril Gina, Martín-Vilchez Samuel, de Miguel Alejandro, Gómez-Fernández Antía, Rodríguez-Lopez Andrea, Soria-Chacartegui Paula, Abad-Santos Francisco, Novalbos Jesús
Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria La Princesa (IIS-Princesa), 28006 Madrid, Spain.
Pharmacology Department, Faculty of Medicine, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain.
Int J Mol Sci. 2024 Dec 30;26(1):260. doi: 10.3390/ijms26010260.
Statins are the primary drugs used to prevent cardiovascular disease by inhibiting the HMG-CoA reductase, an enzyme crucial for the synthesis of LDL cholesterol in the liver. A significant number of patients experience adverse drug reactions (ADRs), particularly musculoskeletal problems, which can affect adherence to treatment. Recent clinical guidelines, such as those from the Clinical Pharmacogenetics Implementation Consortium (CPIC) in 2022, recommend adjusting rosuvastatin doses based on genetic variations in the and genes to minimize ADRs and improve treatment efficacy. Despite these adjustments, some patients still experience ADRs. So, we performed a candidate gene study to better understand the pharmacogenetics of rosuvastatin. This study included 119 healthy volunteers who participated in three bioequivalence trials of rosuvastatin alone or in combination with ezetimibe at the Clinical Trials Unit of the Hospital Universitario de La Princesa (UECHUP). Participants were genotyped using a custom OpenArray from ThermoFisher that assessed 124 variants in 38 genes associated with drug metabolism and transport. No significant differences were observed according to sex or biogeographic origin. A significant increase in t (() = 0.013) was observed in the rosuvastatin plus ezetimibe trial compared with the rosuvastatin alone trials. Genetic analysis showed that decreased (DF) and poor function (PF) volunteers for the ABCG2 transporter had higher AUC/DW (adjusted dose/weight), AUC/DW and C/DW compared to normal function (NF) volunteers (< 0.001). DF and PF volunteers for SLCO1B1 showed an increase in AUC/DW ( = 0.020) compared to increased (IF) and NF individuals. Results for ABCG2 and SLCO1B1 were consistent with the existing literature. In addition, AUC/DW, AUC/DW and C/DW were increased in intermediate (IA) and poor (PA) NAT2 acetylators ( = 0.001, < 0.001, < 0.001, respectively) compared to rapid acetylators (RA), which could be associated through a secondary pathway that was previously unknown.
他汀类药物是用于预防心血管疾病的主要药物，通过抑制3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶发挥作用，该酶对肝脏中低密度脂蛋白胆固醇的合成至关重要。相当数量的患者会出现药物不良反应（ADR），尤其是肌肉骨骼问题，这可能会影响治疗依从性。近期的临床指南，如2022年临床药物基因组学实施联盟（CPIC）发布的指南，建议根据SLCO1B1和ABCG2基因的遗传变异调整瑞舒伐他汀剂量，以尽量减少ADR并提高治疗效果。尽管进行了这些调整，仍有一些患者会出现ADR。因此，我们开展了一项候选基因研究，以更好地了解瑞舒伐他汀的药物遗传学。本研究纳入了119名健康志愿者，他们在拉公主大学医院临床试验单元（UECHUP）参与了三项瑞舒伐他汀单独使用或与依折麦布联合使用的生物等效性试验。使用赛默飞世尔定制的OpenArray对参与者进行基因分型，该技术可评估与药物代谢和转运相关的38个基因中的124个变异。未观察到性别或生物地理来源方面的显著差异。与瑞舒伐他汀单独使用的试验相比，瑞舒伐他汀加依折麦布试验中观察到t（() = 0.013）显著增加。基因分析表明，与正常功能（NF）志愿者相比，ABCG2转运蛋白功能降低（DF）和功能不良（PF）的志愿者具有更高的AUC/DW（调整剂量/体重）、AUC/DW和C/DW（< 0.001）。与功能增加（IF）和NF个体相比，SLCO1B1的DF和PF志愿者的AUC/DW增加（ = = 0.020）。ABCG2和SLCO1B1的结果与现有文献一致。此外，与快速乙酰化者（RA）相比，中间（IA）和慢乙酰化者（PA）的NAT2乙酰化酶的AUC/DW、AUC/DW和C/DW增加（分别为 = 0.001、< 0.001、< 0.001），这可能通过一条先前未知的次要途径相关联。
