Uptake of the nitroimidazole drug megazol by African trypanosomes

Michael P. Barrett (Lead / Corresponding author), Alan H. Fairlamb, Bernard Rousseau, Gerard Chauvière, Jacques Perié

    Research output: Contribution to journalArticlepeer-review

    29 Citations (Scopus)

    Abstract

    Megazol, CL 64,855 (2-amino-5-[1-methyl-5-nitro-2-imidazolyl]-1,3,4-thiazole) has been shown to be extremely effective in clearing experimental infections of African trypanosomes. An unusual amino-purine transporter termed P2, implicated in the transport of both the diamidine and melaminophenyl arsenical classes of drug in Trypanosoma brucei, recognised chemical groups on compounds which are also present on megazol. Megazol interacted with this carrier protein, as judged by its ability to inhibit P2 adenosine transport and to abrogate in vitro arsenical-induced lysis in a dose-dependent manner. However, parasites resistant to melaminophenyl arsenical and diamidine drugs due to lack of the P2 transporter showed no resistance to megazol. This is because passive diffusion represented the major route of entry. Initial rates of uptake were not saturable within the limit of megazol's solubility and did not conform to thermodynamic precepts compatible with carrier-mediated uptake. Adenosine and other P2 transporter substrates, even at high concentration, had little impact on megazol uptake. Uptake was biphasic, with a very rapid equilibration across the membrane followed by a slower accumulation over time. The equilibration phase represented a simple passive diffusion, with the subsequent uptake probably being due to metabolism of the drug. Copyright (C) 2000 Elsevier Science Inc.

    Original languageEnglish
    Pages (from-to)615-620
    Number of pages6
    JournalBiochemical Pharmacology
    Volume59
    Issue number6
    DOIs
    Publication statusPublished - 15 Mar 2000

    Keywords

    • Chemotherapy
    • Drug uptake
    • Megazol
    • Sleeping sickness
    • Trypanosomiasis

    Fingerprint

    Dive into the research topics of 'Uptake of the nitroimidazole drug megazol by African trypanosomes'. Together they form a unique fingerprint.

    Cite this