School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia.
Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria 810107, Nigeria.
Molecules. 2022 Mar 25;27(7):2126. doi: 10.3390/molecules27072126.
Low-dose aspirin (LDA) is the backbone for secondary prevention of coronary artery disease, although limited by gastric toxicity. This study aimed to identify novel metabolites that could predict LDA-induced gastric toxicity using pharmacometabolomics.
Pre-dosed urine samples were collected from male Sprague-Dawley rats. The rats were treated with either LDA (10 mg/kg) or 1% methylcellulose (10 mL/kg) per oral for 28 days. The rats' stomachs were examined for gastric toxicity using a stereomicroscope. The urine samples were analyzed using a proton nuclear magnetic resonance spectroscopy. Metabolites were systematically identified by exploring established databases and multivariate analyses to determine the spectral pattern of metabolites related to LDA-induced gastric toxicity.
Treatment with LDA resulted in gastric toxicity in 20/32 rats (62.5%). The orthogonal projections to latent structures discriminant analysis (OPLS-DA) model displayed a goodness-of-fit (RY) value of 0.947, suggesting near-perfect reproducibility and a goodness-of-prediction (QY) of -0.185 with perfect sensitivity, specificity and accuracy (100%). Furthermore, the area under the receiver operating characteristic (AUROC) displayed was 1. The final OPLS-DA model had an RY value of 0.726 and QY of 0.142 with sensitivity (100%), specificity (95.0%) and accuracy (96.9%). Citrate, hippurate, methylamine, trimethylamine N-oxide and alpha-keto-glutarate were identified as the possible metabolites implicated in the LDA-induced gastric toxicity.
The study identified metabolic signatures that correlated with the development of a low-dose Aspirin-induced gastric toxicity in rats. This pharmacometabolomic approach could further be validated to predict LDA-induced gastric toxicity in patients with coronary artery disease.
小剂量阿司匹林（LDA）是冠心病二级预防的基础，但由于其胃毒性而受到限制。本研究旨在通过药物代谢组学来鉴定可能预测 LDA 诱导的胃毒性的新型代谢物。
预先给雄性 Sprague-Dawley 大鼠喂食剂量的尿液样本。大鼠经口给予 LDA（10mg/kg）或 1%甲基纤维素（10mL/kg），每天 1 次，共 28 天。用立体显微镜检查大鼠的胃是否有胃毒性。使用质子核磁共振波谱分析尿液样本。通过探索已建立的数据库和多元分析来系统地鉴定代谢物，以确定与 LDA 诱导的胃毒性相关的代谢物的光谱模式。
用 LDA 治疗导致 32 只大鼠中的 20 只（62.5%）出现胃毒性。正交投影到潜在结构判别分析（OPLS-DA）模型显示拟合度（RY）值为 0.947，表明具有近乎完美的可重复性和预测度（QY）为-0.185，具有完美的敏感性、特异性和准确性（100%）。此外，接收器操作特征（AUROC）的面积为 1。最终的 OPLS-DA 模型的 RY 值为 0.726，QY 值为 0.142，具有 100%的敏感性、95.0%的特异性和 96.9%的准确性。柠檬酸、马尿酸、甲胺、三甲胺 N-氧化物和α-酮戊二酸被鉴定为与大鼠低剂量阿司匹林诱导的胃毒性发展相关的可能代谢物。
本研究确定了与大鼠低剂量阿司匹林诱导的胃毒性发展相关的代谢特征。这种药物代谢组学方法可以进一步验证，以预测冠心病患者的 LDA 诱导的胃毒性。
