(570i) The Effect of Solvents and Other Parameters On Drug Oxidation Via Biomimetic Catalysis

Up to 50% of drugs commercially available are primarily metabolized by cytochrome P450 enzymes. As a result of these enzymatic drug interactions, reactive intermediates may be generated leading to cellular accumulation and toxicity. The toxicity of these metabolites, specifically hepatotoxicity, is the leading cause of drug attrition. Therefore, the study of these biological transformations is essential in the detection and prediction of reactive metabolites from novel compounds (e.g. pharmaceuticals, synthetic foods). Current screening techniques employ cytochrome P450 in the form of liver conjugates (e.g. microsomes, hepatocytes). These biological methods have been successfully developed for pharmaceutical screening; however, the liver conjugates are often difficult to obtain, expensive to store, and do not produce quantitative results. A number of metalloporphyrin biomimetic systems have been developed with the ability to imitate the kinetic properties offered by the cytochrome P450 metabolism of xenobiotics. Biomimetic systems offer an ideal solution to this problem due to their similar kinetic and selective abilities as their enzyme counterparts with enhanced stability and ease of use. The purpose of this work is to study the effect of solvents and other parameters on the oxidation of various metabolites by iron and manganese metalloporphyrins. The Abraham model will be used to quantify the effect of solvent properties in order to determine the optimum solvent. This optimization will lead to future work towards the development of a cytochrome P450 biomimetic sensor.