Background: 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.
Objective: In this review, we addressed the available evidence on the effects of malaria on drug metabolism activity
and kinetics in rodents and humans.
Results: 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.
Conclusion: 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