Calemi Debora Bressanim de Aquino, Godoi Alexandre Barcia, Minuti Giulia, Neto Fausto Carnevale, Hispagnol Gabriel Felipe, Pilon Alan Cesar, Costa Jose Luiz, Hyslop Stephen, Antunes Natalicia de Jesus
Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-888, SP, Brazil.
Centro de Informação e Assistência Toxicológica (CIATox) de Campinas, Universidade Estadual de Campinas (UNICAMP), Campinas 13083-888, SP, Brazil.
Pharmaceutics. 2025 May 2;17(5):601. doi: 10.3390/pharmaceutics17050601.
: Malaria significantly impacts the health of populations living in poverty and vulnerable conditions. Resistance to current antimalarial drugs remains a major challenge and highlights the urgent need for novel, effective, and safer therapies. Violacein, a purple pigment, has demonstrated potent antiplasmodial activity, making it a promising antimalarial candidate. However, to date, no in vitro metabolism studies of violacein have been published. In this study, the metabolic stability of violacein was evaluated using human (HLMs), mouse (MLMs), and rat (RLMs) liver microsomes and the metabolites generated by HLMs and RLMs were assessed. : Liquid chromatography quadrupole mass spectrometry (LC-MS/MS) was used to investigate the metabolic stability of violacein, while liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) was used to identify the metabolites. In silico analyses were used to support in vitro metabolite identification by providing insights into potential metabolic pathways and predicting metabolite structures, thereby enhancing the accuracy and efficiency of the identification process. : The half-life (t) for violacein in RLMs, MLMs, and HLMs was 36, 81, and 216 min, respectively. The in vitro intrinsic clearance (CL) values were 38.4, 17.0, and 6.4 µL/min/mg for RLMs, MLMs, and HLMs, respectively, while the in vivo intrinsic clearance (CL) was 93.7, 67.0, and 6.6 mL/min/kg, respectively. A slow elimination profile was observed in HLMs followed by MLMs, with rapid elimination in RLMs, indicating greater stability of violacein in HLMs and MLMs when compared with RLMs. Four violacein metabolites were identified in HLMs and RLMs, two of which were formed by phase I metabolism, one by phase II metabolism, and one by phase I + II metabolism. : This study provides the first published analysis of the metabolic stability of violacein.
疟疾对生活在贫困和脆弱环境中的人群的健康有重大影响。对当前抗疟药物的耐药性仍然是一个主要挑战，凸显了对新型、有效和更安全疗法的迫切需求。紫菌素是一种紫色色素，已显示出强大的抗疟原虫活性，使其成为一种有前景的抗疟候选药物。然而，迄今为止，尚未发表关于紫菌素的体外代谢研究。在本研究中，使用人肝微粒体（HLMs）、小鼠肝微粒体（MLMs）和大鼠肝微粒体（RLMs）评估了紫菌素的代谢稳定性，并对HLMs和RLMs产生的代谢产物进行了评估。：采用液相色谱-四极杆质谱（LC-MS/MS）研究紫菌素的代谢稳定性，同时采用液相色谱-四极杆飞行时间质谱（LC-QTOF-MS）鉴定代谢产物。通过计算机分析为体外代谢产物鉴定提供支持，深入了解潜在的代谢途径并预测代谢产物结构，从而提高鉴定过程的准确性和效率。：紫菌素在RLMs、MLMs和HLMs中的半衰期（t）分别为36、81和216分钟。RLMs、MLMs和HLMs的体外固有清除率（CL）值分别为38.4、17.0和6.4 μL/min/mg，而体内固有清除率（CL）分别为93.7、67.0和6.6 mL/min/kg。在HLMs中观察到缓慢的消除过程，其次是MLMs，而在RLMs中则快速消除，这表明与RLMs相比，紫菌素在HLMs和MLMs中具有更高的稳定性。在HLMs和RLMs中鉴定出四种紫菌素代谢产物，其中两种由I相代谢形成，一种由II相代谢形成，一种由I + II相代谢形成。：本研究首次发表了对紫菌素代谢稳定性的分析。
