Alteration of drug metabolism can have a major impact on drug therapy versus drug toxicity. We will determine if inhibition of the metabolism of 1-alpha-acetylmethadol (LAAM) will result in a decrease of its pharmacodynamic effect. LAAM is sequetially N- demethylated to the active metabolites norLAAM and dinorLAAM. Our preliminary data support the role of cytochrome P-450 3A4 (P450 3A4) in both of these reactions. P450 3A4 is inihibited by a number of medications including ketoconazole. The importance of norLAAM and dinorLAAM in the pharmacokinetics and pharmacodynamic efficts of LAAM are estblished. The following experiments will test our hypothesis that inihibition of LAAM metabolism will decrease its pharmacodynamic activity, as well as determine the mechanism for such an effect. Michaelis-Menten kinetics of LAAM and for LAAM N-demethylation will be determined in human liver microsomes to estimate their contribution to the intrinsic clearance (Vmax/Km) of LAAM and determine optimal substrate concentrations for subsequent experiments. The role of P450 3A4 in these reactions will then be confirmed by selective inhibition of the N-demethylations in human livermicrosomes, correlation of the inter-individual variation of these reactions with the variation in isozyme-selective activities in human liver microsomes, and determination of the rates of N- demethylation by cDNA-expressed human P450s. Our hypothesis will then be tested in humans given a single oral dose of LAAM with or without ketoconazole. We predict ketoconazole will increase the half-life of LAAM, decrease the productio of norLAAM and dinorLAAM and dimnish a pharmacodynamic endpoint, pupillary constriction. These in vitro and in vivo studies are important to establish the safety and efficacy of LAAM under conditions of potential drug interaction.
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