Department of Biological Sciences, National School of Public Health, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.
Curr Drug Metab. 2021;22(2):127-138. doi: 10.2174/1389200221999210101232057.
Infections and inflammation lead to a downregulation of drug metabolism and kinetics in experimental animals. These changes in the expression and activities of drug-metabolizing enzymes may affect the effectiveness and safety of pharmacotherapy of infections and inflammatory conditions.
In this review, we addressed the available evidence on the effects of malaria on drug metabolism activity and kinetics in rodents and humans.
An extensive literature review indicated that infection by Plasmodium spp consistently decreased the activity of hepatic Cytochrome P450s and phase-2 enzymes as well as the clearance of a variety of drugs in mice (lethal and non-lethal) and rat models of malaria. Malaria-induced CYP2A5 activity in the mouse liver was an exception. Except for paracetamol, pharmacokinetic trials in patients during acute malaria and in convalescence corroborated rodent findings. Trials showed that, in acute malaria, clearance of quinine, primaquine, caffeine, metoprolol, omeprazole, and antipyrine is slower and that AUCs are greater than in convalescent individuals.
Notwithstanding the differences between rodent models and human malaria, studies in P. falciparum and P. vivax patients confirmed rodent data showing that CYP-mediated clearance of antimalarials and other drugs is depressed during the symptomatic disease when rises in levels of acute-phase proteins and inflammatory cytokines occur. Evidence suggests that inflammatory cytokines and the interplay between malaria-activated NF-kB-signaling and cell pathways controlling phase 1/2 enzyme genes transcription mediate drug metabolism changes. The malaria-induced decrease in drug clearance may exacerbate drug-drug interactions, and the occurrence of adverse drug events, particularly when patients are treated with narrow-margin-of-safety medicines.
感染和炎症会导致实验动物的药物代谢和动力学下调。这些药物代谢酶的表达和活性的变化可能会影响感染和炎症情况下药物治疗的效果和安全性。
在本综述中，我们探讨了疟疾对啮齿动物和人类药物代谢活性和动力学的影响的现有证据。
广泛的文献回顾表明，疟原虫感染一致降低了肝细胞色素 P450s 和相 2 酶的活性以及各种药物在小鼠（致死性和非致死性）和鼠疟疾模型中的清除率。疟疾诱导的小鼠肝脏 CYP2A5 活性是一个例外。除了对乙酰氨基酚外，急性疟疾和恢复期患者的药代动力学试验证实了啮齿动物的发现。试验表明，在急性疟疾中，奎宁、伯氨喹、咖啡因、美托洛尔、奥美拉唑和安替比林的清除率较慢，AUC 大于恢复期个体。
尽管啮齿动物模型和人类疟疾之间存在差异，但对恶性疟原虫和间日疟原虫患者的研究证实了啮齿动物的数据，表明在出现急性相蛋白和炎症细胞因子升高的症状性疾病期间，CYP 介导的抗疟药和其他药物的清除率降低。有证据表明，炎症细胞因子以及疟疾激活的 NF-kB 信号转导和控制相 1/2 酶基因转录的细胞途径之间的相互作用介导了药物代谢的变化。药物清除率的降低可能会加剧药物相互作用和不良药物事件的发生，尤其是当患者接受安全性边际较窄的药物治疗时。
