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The binding ability of alpha-1-acid glycoprotein as a mechanism of resistance to methadone
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The binding ability of alpha-1-acid glycoprotein as a mechanism of resistance to methadone
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Dissertation
The binding ability of alpha-1-acid glycoprotein as a mechanism of resistance to methadone
2010
Overview
Dependence on heroin and other opioids represents a considerable problem worldwide. There is a continual need to improve therapy and/ or find more efficacious alternatives if these issues are to be addressed. The most commonly implemented pharmacological therapy in treating said dependencies is methadone; however its success is the subject of ongoing debate. Certain plasma proteins including alpha1-acid glycoprotein (AGP) bind to drugs which causes inactivation and, if low enough, may prevent a therapeutic effect being attained. The hepatic synthesis of AGP increases two- to five-fold during numerous physiological and pathophysiological conditions, becoming the most prevalent acute phase protein in the blood. Additionally, the structure of the sugar chains (glycans) attached to the surface of underlying polypeptide backbones can differ, potentially altering the functions performed. AGP was isolated from blood samples obtained from patients undergoing various stages and types of opioid-replacement therapy and from heparinised blood samples provided by the Blood Transfusion Service. Structural analysis of the glycans was undertaken primarily through the use of high pH anion-exchange chromatography (HPAEC) and intrinsic fluorescence used as a measure of drug binding. The composition of glycans attached to the polypeptide backbone of AGP isolated from patient samples was found to markedly differ from that of a ‘normal' healthy population. Levels of galactose and N-acetyl-glucosamine were amplified in all methadone treatment groups which suggested increased branching of glycans; this was supported by HPAEC analysis of complete glycan chains. Binding of methadone to all isolated AGP samples was elevated at the highest drug concentrations tested; however the degree of quenching appeared to be greater in patients. Therefore, the glycoforms expressed by AGP appear to be associated with the subsequent binding of the glycoprotein to methadone. It is possible that altered glycosylation could increase affinity for the drug, reducing its bioactive concentration to below that required to produce the pharmacological effect. Currently, the doses of methadone used in opioid replacement therapy are primarily influenced by the expression of physical symptoms, however this preliminary study has indicated that determination of the level and glycoform expression of AGP may offer potential use when determining the most effective therapy and dosage regimen.
Publisher
ProQuest Dissertations & Theses
Subject
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