A non-lethal malarial infection results in reduced drug metabolizing enzyme expression and drug clearance in mice.

Autor: Mimche SM; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA., Lee CM; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA., Liu KH; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA., Mimche PN; Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA., Harvey RD; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA., Murphy TJ; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA., Nyagode BA; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA., Jones DP; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA., Lamb TJ; Division of Infectious Diseases, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA., Morgan ET; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA. etmorga@emory.edu.
Jazyk: angličtina
Zdroj: Malaria journal [Malar J] 2019 Jul 12; Vol. 18 (1), pp. 234. Date of Electronic Publication: 2019 Jul 12.
DOI: 10.1186/s12936-019-2860-5
Abstrakt: Background: 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. Previous studies have shown reduced clearance of quinine, a treatment for Plasmodium infection, in individuals with malaria.
Methods: The 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.
Results: The 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%.
Conclusions: These 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.
Databáze: MEDLINE
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