METABOLISM IN HUMAN OXIDATIVE PHENOTYPES AND THEIR RAT MODELS
Methoxyphenamine (MP), which is a ß2 agonist used clinically as a bronchodilator, is marketed in Canada in the combination non-prescription product, Orthoxicol™. It has been shown to be metabolized by three phase I metabolic pathways, namely, N-demethylation (NDMP), 0-demethylation (0DMP) and aromatic 5-hydroxylation (5HMP). Genetic polymorphism in the metabolism of MP and its relationship to debrisoquine (D) oxidation to 4-41ydroxy-debrisoquine (4HD) were investigated inhuman as well as rat models of human debrisoquine phenotypes. Such a study enabled investigation of the effects on the alternative metabolic pathways when one or more metabolic reaction of MP are genetically impaired. In order to perform the above studies, quantitative gas-liquid chranatographic (GLC) procedures for MP and three of its metabolites in biological fluids were developed. The metabolites in plasma were measured using an electron-capture detector (ECU). The lower limit of quantitation for each metabolite was less than 4 ng m1-1 of plasma, with a coefficient of variation less than 10% in each case. The poor electron-capture response of fluorinated derivatives of MP necessitated the use of nitrogen-phosphorous detection (NPD). Extractive derivatization with pentafluorcbenzoyl chloride, without the need for protein precipitation, enabled quantitation of MP down to 3.8 ng ml-1 from a 2-mi aliquot of plasma. The urinary concentration of MP and its three metabolites were determined simultaneously after derivatization with trifluoroacetic anhydride by a modified literature procedure which employed GLC-NPD.
Doctor of Philosophy (Ph.D.)
Pharmacy and Nutrition