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Isometamidium metabolism and distribution in rat hepatocytes

Boibessot, I. and Grant, M.H. and Skellern, G.G. and Watson, D.G. (2001) Isometamidium metabolism and distribution in rat hepatocytes. In: 26th Meeting of the International Scientific Council for Trypanosomiasis Research and Control, 2001-10-01 - 2001-10-05, Ouagadougou.

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Abstract

Little is known about the metabolism and mechanism of action of the trypanocide, isometamidium (ISM), the major drug used for prophylaxis of trypanosomiasis. We have investigated its metabolism and distribution in isolated rat hepatocytes using liquid chromatography-mass spectrometry and confocal laser scanning microscopy (CLSM). Two putative metabolites were formed, which were proposed to be a mono-acetyl derivative and an oxidized metabolite (SII). This is the first demonstration of the hepatic metabolism of ISM, as previous in vivo studies were hampered by dose-limiting toxicity and insensitive analytical methods. The intrinsic fluorescence of the drug enabled its intracellular uptake to be followed by CLSM. It is taken up rapidly into the nucleolus, nuclear membrane and endoplasmic reticulum within 5 min, and retained in the nucleus for at least 24 h. Persistent binding of ISM to cellular macromolecules may contribute to its prophylactic effect in vivo. Pretreatment of rats with 3-methylcholanthrene, phenobarbitone (PB) or the widely used pyrethroid pesticide, deltamethrin, resulted in an increase in metabolism of ISM to the proposed SII after 1 h incubation with hepatocytes. 3-methylcholanthrene was the most potent inducer, causing a maximal 19.5-fold induction of SII formation after exposure of hepatocytes to ISM for 1 h compared with formation by control hepatocytes. In comparison, at the 1 h timepoint deltamethrin pre-treatment caused a 10.2-fold induction, and PB only 8.2 fold.

Item type: Conference or Workshop Item (Paper)
ID code: 8428
Notes: I. Boibessot, I., Tettey, J.N.A., Skellern, G.G., WATSON, D.G., Grant, M.H. Metabolism of isometamidium in hepatocytes isolated from control and inducer-treated rats. Journal of Veterinary Pharmacology and Therapeutics Volume 29 Issue 6, Pages 547 - 553
Keywords: isometamidium metabolism, rat hepatocytes, bioengineering, trypanocide, Bioengineering
Subjects: Technology > Engineering (General). Civil engineering (General) > Bioengineering
Department: Faculty of Engineering > Bioengineering
Unknown Department
Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
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Depositing user: Strathprints Administrator
Date Deposited: 10 Aug 2009 14:55
Last modified: 04 Oct 2012 17:09
URI: http://strathprints.strath.ac.uk/id/eprint/8428

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