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Microbial Metabolism of Atovaquone and Cytotoxicity of the Produced Phase I Metabolite
Background and Objectives Atovaquone is a hydroxynaphthoquinone with selective action in the mitochondrial respiratory chain of malaria parasite. It is employed for both the treatment and prevention of malaria, in a combination with proguanil. The aim of this study was to elucidate the in vitro meta...
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Published in: | European journal of drug metabolism and pharmacokinetics 2016-10, Vol.41 (5), p.645-650 |
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Main Authors: | , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Background and Objectives
Atovaquone is a hydroxynaphthoquinone with selective action in the mitochondrial respiratory chain of malaria parasite. It is employed for both the treatment and prevention of malaria, in a combination with proguanil. The aim of this study was to elucidate the in vitro metabolites from atovaquone and to evaluate their cytotoxic activities.
Methods
The biotransformation of atovaquone was performed using
Mucor rouxii
NRRL 1894,
Cunninghamella echinulata
var.
elegans
ATCC 8688a and
C. elegans
ATCC 10028b, which have been reported as microbial models of mammalian drug metabolism. Experiments were also carried out with two probiotic strains from the human intestinal tract:
Bifidobacterium
sp. and
Lactobacillus acidophilus
. The phase I metabolite was isolated, its chemical structure was elucidated and its toxicity was evaluated using the neoplastic cell line SKBR-3 derived from human breast cancer and normal human fibroblast cell line GM07492-A. Cell cytotoxicity assays were also carried out with atovaquone.
Result
Only the fungi were able to convert atovaquone to metabolite trans-3-[4′-(4″-chlorophenyl)cyclohexyl)-1,2-dioxo-dihydro-1H-indene-3-carboxylic acid. The metabolite displayed 50 % inhibitory concentration (IC
50
) values of 110.20 ± 2.2 and 108.80 ± 1.5 µmol/L against breast cancer cell line SKBR-3 and fibroblasts cell line GM07492-A, respectively. The IC
50
values of atovaquone were 282.30 ± 1.8 and 340.50 ± 1.4 µmol/L against breast cancer and normal fibroblasts cell lines, respectively.
Conclusions
The produced metabolite was more toxic than atovaquone and was not selective to normal or cancer cell lines. The present study is the first to report the production of atovaquone metabolite. |
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ISSN: | 0378-7966 2107-0180 |
DOI: | 10.1007/s13318-015-0294-1 |