Abstract
BackgroundThe naturally occurring alkaloid drug, quinine is commonly used for the treatment of severe malaria. Despite centuries of use, its metabolism is still not fully understood, and may play a role in the haemolytic disorders associated with the drug.MethodsIncubations of quinine with CYPs 1A2, 2C9, 2C19, 2D6, and 3A4 were conducted, and the metabolites were characterized by accurate mass UPLC-MSE analysis. Reactive oxygen species generation was also measured in human erythrocytes incubated in the presence of quinine with and without microsomes.ResultsThe metabolites 3-hydroxyquinine, 2’-oxoquininone, and O-desmethylquinine were observed after incubation with CYPs 3A4 (3-hydroxyquinine and 2’-oxoquininone) and 2D6 (O-desmethylquinine). In addition, multiple hydroxylations were observed both on the quinoline core and the quinuclidine ring system. Of the five primary abundance CYPs tested, 3A4, 2D6, 2C9, and 2C19 all demonstrated activity toward quinine, while 1A2 did not. Further, quinine produced robust dose-dependent oxidative stress in human erythrocytes in the presence of microsomes.ConclusionsTaken in context, these data suggest a CYP-mediated link between quinine metabolism and the poorly understood haemolytic condition known as blackwater fever, often associated with quinine ingestion.
Highlights
The naturally occurring alkaloid drug, quinine is commonly used for the treatment of severe malaria
In order to determine the specific metabolites likely to be formed physiologically by each of the five primary abundance Cytochrome P450 (CYP) (1A2, 3A4, 2C9, 2C19, and 2D6), 1-hr incubations with quinine were conducted and the subsequent metabolites formed were analysed by accurate mass Ultra performance liquid chromatography (UPLC)-MSE
The cinchona alkaloid anti-malarial agent, quinine is extensively metabolized in vivo, and many of the resulting metabolites have been reported both in urine and plasma [4,7,8,16]
Summary
The naturally occurring alkaloid drug, quinine is commonly used for the treatment of severe malaria. Usage of the alkaloid anti-malarial agent, quinine to treat resistant strains of Plasmodium falciparum and as an intravenous treatment for severe malaria has increased over the past few decades [1,2,3,4]. Several in vitro and in vivo studies have reported numerous metabolites of quinine, including 3-hydroxyquinine, O-desmethylquinine, and 2’-oxoquininone and speculations have been made concerning their origins. Wanwimolruk et al have shown that, while pretreatment with the CYP 3A4 inducer, rifampin seemed to enhance quinine clearance, no appreciable changes in 3-hydroxyquinine formation were noted after such treatment [4,8].
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