Abstract
BackgroundGiven the central importance of anti-malarial drugs in the treatment of malaria, there is a need to understand the effect of Plasmodium infection on the broad spectrum of drug metabolizing enzymes. Previous studies have shown reduced clearance of quinine, a treatment for Plasmodium infection, in individuals with malaria.MethodsThe hepatic expression of a large panel of drug metabolizing enzymes was studied in the livers of mice infected with the AS strain of Plasmodium chabaudi chabaudi, a nonlethal parasite in most strains of mice with several features that model human Plasmodium infections. C57BL/6J mice were infected with P. chabaudi by intraperitoneal injection of infected erythrocytes and sacrificed at different times after infection. Relative hepatic mRNA levels of various drug metabolizing enzymes, cytokines and acute phase proteins were measured by reverse transcriptase-real time PCR. Relative levels of cytochrome P450 proteins were measured by Western blotting with IR-dye labelled antibodies. Pharmacokinetics of 5 prototypic cytochrome P450 substrate drugs were measured by cassette dosing and high-resolution liquid chromatography-mass spectrometry. The results were analysed by MANOVA and post hoc univariate analysis of variance.ResultsThe great majority of enzyme mRNAs were down-regulated, with the greatest effects occurring at the peak of parasitaemia 8 days post infection. Protein levels of cytochrome P450 enzymes in the Cyp 2b, 2c, 2d, 2e, 3a and 4a subfamilies were also down-regulated. Several distinct groups differing in their temporal patterns of regulation were identified. The cassette dosing study revealed that at the peak of parasitaemia, the clearances of caffeine, bupropion, tolbutamide and midazolam were markedly reduced by 60–70%.ConclusionsThese findings in a model of uncomplicated human malaria suggest that changes in drug clearance in this condition may be of sufficient magnitude to cause significant alterations in exposure and response of anti-malarial drugs and co-medications.
Highlights
Given the central importance of anti-malarial drugs in the treatment of malaria, there is a need to understand the effect of Plasmodium infection on the broad spectrum of drug metabolizing enzymes
The evidence collectively suggests that Plasmodium infection has a significant effect on the regulation of the cytochrome P450 (CYP) family of drug metabolizing enzyme (DME)
One study found that in rats infected with the ANKA strain of P. berghei, total hepatic microsomal P450 was reduced by 56%, and CYP3A2 protein by 32%, whereas CYP2E1 protein was unaffected
Summary
Given the central importance of anti-malarial drugs in the treatment of malaria, there is a need to understand the effect of Plasmodium infection on the broad spectrum of drug metabolizing enzymes. The evidence collectively suggests that Plasmodium infection has a significant effect on the regulation of the cytochrome P450 (CYP) family of DMEs. CYP3A enzymes are mainly responsible for quinine clearance via its 3-hydroxylation [8], indirectly suggesting that expression of CYP3A may be reduced in Plasmodiuminfected individuals. One study found that in rats infected with the ANKA strain of P. berghei, total hepatic microsomal P450 was reduced by 56%, and CYP3A2 protein by 32%, whereas CYP2E1 protein was unaffected. In agreement with these findings, testosterone 6β-hydroxylation (CYP3A2) was reduced by 41% and chlorzoxazone hydroxylation (CYP2E1) was unchanged [19]. In pregnant mice infected with P. berghei, a 65% down-regulation of Cyp3a11 mRNA was reported, together with both down-and up-regulation of different members of the ABC family of drug transporters [20]
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