HPLC Determination of Terfenadine Metabolism by P450 Enzymes : An Assay for P450 4F12 Enzyme Activity and Organic Solvent Effects
Meyers, Jacob I.
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Cytochrome P450 enzymes are heme-containing oxidoreductases involved in the metabolism of both endogenous and exogenous compounds in the human body. One class of exogenous compounds known to be metabolized by P450s is pharmaceutical agents. When P450 metabolism of pharmaceutical agents are studied in vitro they are often done in organic solvents, which are necessary to dissolve most drugs into solution. Previous research has shown that organic solvents can have adverse effects on P450 metabolism, depending on the organic solvent and the P450. These adverse effects include activation, inhibition, and no effect on enzyme activity. This research sought to elucidate the effect of DMSO on P450 4F12 activity, by looking at its metabolism of one of its known substrates, the pharmaceutical drug terfenadine, in the presence of varying levels of DMSO. The results show that the effects were negligible. The levels of terfenadine samples in 1.0% and 2.0% DMSO never varied by more than 3% when compared to the amount of terfenadine in the control though there was a nearly 20% decrease in 4F12 activity in the 0.5% DMSO sample However since this only seen at 0.5% DMSO and not in samples containing higher concentrations of DMSO, it can be assumed that DMSO has no affect on P450 4F12 metabolism of terfenadine. The terfenadine metabolite levels did not follow the expected results as the concentration of metabolite appeared to increase with increasing levels of DMSO. This is unusual as it was expected that the levels would not change since the terfenadine levels were fairly consistent. The changes may be due to the low concentration of metabolite found in the control. Therefore any small change in terfenadine metabolite levels in the other samples would cause a large change in the relative amount of terfenadine metabolite. This could be due to imprecision in the determination of the peak area, or noise from impurities affecting the baseline. Despite this, the evidence from the terfenadine samples demonstrates that the effects of DMSO on P450 4F12 metabolism of terfenadine are negligible and does not effect the performance and efficiency of enzymatic capabilities of P450 4F12.
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