Oxidation of Clozapine and Ascorbate by Myeloperoxidase

The kinetics and spectra of the reactions of clozapine with compounds I and II of myeloperoxidase were investigated using both single- and sequential-mixing stopped-flow techniques, steady-state kinetics, and spectrophotometric measurements. The results show conclusively that both compounds I and II are reduced in one-electron reactions with clozapine. At pH 7.0 the rate constant for compound I reacting with clozapine is (1.5 ± 0.1) × 106 M−1 s−1 and for compound II (4.8 ± 0.1) × 104 M−1 s−1. The physiological pH of 7.4 was found to be optimal for the oxidation of clozapine by compound I. The rate constant for compound I reacting with ascorbate is (1.1 ± 0.1) × 106 M−1 s−1 and for compound II (1.1 ± 0.2) × 104 M−1 s−1, both obtained at pH 7.0. Experiments with both clozapine and ascorbate present showed that ascorbate acts both as a competitive inhibitor and free radical scavenger.