Laboratory of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece.
Laboratory of Pharmacology, Department of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece.
Int J Mol Sci. 2023 Sep 12;24(18):13966. doi: 10.3390/ijms241813966.
(1) Carfilzomib (Cfz) is an antineoplastic agent indicated for the treatment of multiple myeloma. However, its beneficial action is attenuated by the occurrence of cardiotoxicity and nephrotoxicity as the most common adverse effects. Presently, there is well-established knowledge on the pathomechanisms related to these side effects; however, the research on the metabolic alterations provoked by the drug is limited. (2) An in vivo simulation of Cfz-induced toxicity was developed in (i) Cfz-treated and (ii) control mice. An RP-HRMS-based protocol and an advanced statistical treatment were used to investigate the impact of Cfz on the non-polar metabolome. (3) The differential analysis classified the Cfz-treated and control mice and resulted in a significant number of identified biomarkers with AUC > 0.9. The drug impaired the biosynthesis and degradation of aromatic amino acids (AAA) and led to alterations of uremic toxins in the renal and urine levels. Furthermore, the renal degradation of tryptophan was affected, inducing its degradation via the kynurenine pathway. (4) The renal levels of metabolites showed impaired excretion and degradation of AAAs. Cfz was, finally, correlated with the biosynthesis of renal dopamine, explaining the biochemical causes of water and ion retention and the increase in systolic pressure.
(1) 卡非佐米（Cfz）是一种抗肿瘤药物，适用于多发性骨髓瘤的治疗。然而，其作为最常见的不良反应的心脏毒性和肾毒性会削弱其有益作用。目前，人们对这些副作用的发病机制有了明确的认识；然而，关于药物引起的代谢改变的研究是有限的。(2) 在（i）Cfz 处理和（ii）对照小鼠中建立了 Cfz 诱导毒性的体内模拟。采用基于 RP-HRMS 的方案和先进的统计处理来研究 Cfz 对非极性代谢组的影响。(3) 差异分析对 Cfz 处理组和对照组的小鼠进行分类，得到了大量 AUC>0.9 的鉴定生物标志物。该药物损害了芳香族氨基酸（AAA）的生物合成和降解，并导致肾脏和尿液水平的尿毒症毒素发生变化。此外，色氨酸的肾脏降解受到影响，通过犬尿氨酸途径诱导其降解。(4) 肾脏水平的代谢物显示出 AAA 的排泄和降解受损。Cfz 与肾多巴胺的生物合成有关，解释了水和离子潴留以及收缩压升高的生化原因。
