OXIDATION OF AGRANULOCYTOSIS CAUSING DRUGS BY MYELOPEROXIDASE

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Myeloperoxidase, an abundant neutrophil protein involved in microbial killing and inflammatory tissue damage, is capable of oxidizing biological molecules and drugs in the presence of H2O2. The required H2O2 is supplied in vivo as a secondary product of the respiratory burst. Hypochlorous acid (HOCl) is also a potent oxidant and can be formed in the presence of myeloperoxidase, H2O2 and Cl-. OPC-8212 is a new positive inotropic agent currently undergoing clinical trials in the US for use in the treatment of congestive heart failure. In previous trials, OPC-8212 has been linked to the onset of agranulocytosis in 14% of the patients receiving the drug. Of those patients displaying signs of agranulocytosis, 75% had received an influenza vaccine either just prior to or during the trial, which may have stimulated the neutrophils. To probe this system, EPR (electron paramagnetic resonance spectroscopy) and oxygen uptake will be used. To elucidate whether it is the myeloperoxidase responsible for the oxidation of this drug or the secondary oxidant, hypochlorous acid, two buffer systems, a phosphate buffer containing no chloride ions and a phosphate buffered saline solution were used.