Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida Gainesville, FL, USA.
Front Pharmacol. 2013 Nov 26;4:147. doi: 10.3389/fphar.2013.00147. eCollection 2013.
Pioglitazone is the most widely used thiazolidinedione and acts as an insulin-sensitizer through activation of the Peroxisome Proliferator-Activated Receptor-γ (PPARγ). Pioglitazone is approved for use in the management of type 2 diabetes mellitus (T2DM), but its use in other therapeutic areas is increasing due to pleiotropic effects. In this hypothesis article, the current clinical evidence on pioglitazone pharmacogenomics is summarized and related to variability in pioglitazone response. How genetic variation in the human genome affects the pharmacokinetics and pharmacodynamics of pioglitazone was examined. For pharmacodynamic effects, hypoglycemic and anti-atherosclerotic effects, risks of fracture or edema, and the increase in body mass index in response to pioglitazone based on genotype were examined. The genes CYP2C8 and PPARG are the most extensively studied to date and selected polymorphisms contribute to respective variability in pioglitazone pharmacokinetics and pharmacodynamics. We hypothesized that genetic variation in pioglitazone pathway genes contributes meaningfully to the clinically observed variability in drug response. To test the hypothesis that genetic variation in PPARG associates with variability in pioglitazone response, we conducted a meta-analysis to synthesize the currently available data on the PPARG p.Pro12Ala polymorphism. The results showed that PPARG 12Ala carriers had a more favorable change in fasting blood glucose from baseline as compared to patients with the wild-type Pro12Pro genotype (p = 0.018). Unfortunately, findings for many other genes lack replication in independent cohorts to confirm association; further studies are needed. Also, the biological functionality of these polymorphisms is unknown. Based on current evidence, we propose that pharmacogenomics may provide an important tool to individualize pioglitazone therapy and better optimize therapy in patients with T2DM or other conditions for which pioglitazone is being used.
吡格列酮是最广泛使用的噻唑烷二酮类药物，通过激活过氧化物酶体增殖物激活受体-γ（PPARγ）发挥胰岛素增敏作用。吡格列酮已被批准用于 2 型糖尿病（T2DM）的治疗，但由于其多种疗效，在其他治疗领域的应用正在增加。在这篇假设性文章中，总结了吡格列酮药物基因组学的当前临床证据，并将其与吡格列酮反应的可变性相关联。人类基因组中的遗传变异如何影响吡格列酮的药代动力学和药效学进行了检查。对于药效学作用，检查了基于基因型的吡格列酮的降糖和抗动脉粥样硬化作用、骨折或水肿风险以及对体重指数的影响。迄今为止，CYP2C8 和 PPARG 基因是研究最广泛的基因，选定的多态性有助于吡格列酮药代动力学和药效学的各自变异性。我们假设，吡格列酮途径基因的遗传变异对药物反应的临床观察到的可变性有重要意义。为了检验 PPARG 基因遗传变异与吡格列酮反应变异性相关的假设，我们进行了荟萃分析，以综合目前关于 PPARG p.Pro12Ala 多态性的可用数据。结果表明，与野生型 Pro12Pro 基因型的患者相比，PPARG 12Ala 携带者的空腹血糖从基线的变化更有利（p = 0.018）。不幸的是，许多其他基因的发现缺乏独立队列的复制以确认关联；需要进一步的研究。此外，这些多态性的生物学功能尚不清楚。基于目前的证据，我们提出药物基因组学可能为个体化吡格列酮治疗提供重要工具，并更好地优化 T2DM 或其他使用吡格列酮的疾病患者的治疗。
