Evaluation of the biochemical mechanisms involved in methadone failure in vivo.

Although methadone failure has been studied, the contribution of plasma binding proteins like AGP (α1-acid-glycoprotein) has not been thoroughly examined. For a drug to confer a desired therapeutic effect it must reach a minimal effective concentration (MEC) at its site of action, often accessed via the bloodstream. It is proposed that when plasma AGP concentration increases, like in the acute phase response to stress and inflammation (Elliott et al., 1997, Paterson et al., 2003) more methadone binds the protein and so there is less free (unbound) drug available to bind receptors and achieve the desired therapeutic effect. This could cause therapy failure with patients taking additional opiates to compensate; Methadone Maintenance is a corrective, not a permanent curative procedure (Sees et al., 2000).

The aim of this research is to determine, in a sample of people undergoing methadone therapy, whether there are individual differences in the concentration and glycosylation pattern of the plasma protein AGP. Also, the extent it binds methadone will be investigated to determine whether the MEC is reduced and therefore the therapeutic effect.

It is hypothesised that there will be an increased concentration of AGP present in the samples which will cause a decrease in the concentration of free methadone available to bind receptors. Therefore the normal pharmaco-logical effect is lost causing the therapy to fail (individuals would take additional opiates).

The work is being carried out at School of Life Sciences, Napier University, Edinburgh who is working in conjunction with Dr Malcolm Bruce, Consultant Psychiatrist in Addiction, Community Drug Problem Service, 22-24 Spittal Street, Edinburgh, EH3 9DU and is being funded by the Carnegie Trust.

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