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Identification and Modulation of Esterases Involved in the Metabolism of Heroin

Hauan, Karine Margrethe
Master thesis
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MasterKarine.pdf (2.061Mb)
Year
2014
Permanent link
http://urn.nb.no/URN:NBN:no-44141

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  • Toksikologi [75]
Abstract
Heroin is the main abused opioid, and is causing most drug use related deaths in the European Union and in the USA. New treatment strategies for heroin addiction are needed, and an alternative could be modulation of the enzymes involved in the heroin metabolism with the objective of reducing the rewarding effects of the drug. Different esterases have been shown to be involved in the metabolism of heroin. However, little is known about the importance of these enzymes in the heroin metabolism in organs other than blood. The aim of this study was to identify the esterases involved in heroin metabolism in liver, lung and brain tissue from rat and investigate whether modulation of these enzymes could decrease the effects of heroin in mice, by reducing the concentration of the active metabolite 6MAM. In vitro heroin metabolism studies were conducted in perfused rat liver, lung and brain tissue in the presence and absence of specific esterase inhibitors. This was followed by in vivo experiments in mice, where the effect of specific esterase inhibitors on the heroin metabolism and the heroin induced behavior were investigated. This was examined by combining a behavioral test and measurements of the heroin metabolites in blood and brain. LC-MS/MS was used to quantify heroin and heroin metabolites in the biological matrices. The results suggest that there are different enzymes metabolizing heroin in liver, lung and brain tissue. In liver and lung tissue mainly carboxylesterase is involved, while in brain mainly acetylcholinesterase and butyrylcholinesterase are involved. Administration of esterase inhibitors to mice did not affect the behavior as a result of reduced levels of 6MAM. Increased knowledge of the enzymes involved in metabolism of heroin is important and could lead to other pharmacokinetic treatment approaches.
 
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