Isolation and characterization of sulphoxidation metabolites of moricizine in rat and human biological fluids

The sulphoxidation metabolites of moricizine, moricizine sulphoxide (M-sulphoxide) and moricizine sulphone (M-sulphone) were isolated and identified in the rat bile and urine and in human plasma and urine following administration of moricizine hydrochloride. The sulphoxide and sulphone were synthesized chemically by peroxidation of moricizine hydrochloride with hydrogen peroxide at 25°C and 60°C, respectively, and were characterized by melting point determination (MP), infrared spectroscopy (IR), mass spectroscopy (MS), thin layer chromatography (TLC) and high performance liquid chromatography (HPLC). In the rats (n = 7), which were kept in metabolic cages and given intravenous moricizine (0.72 mg), the mean ± SD percentages recovered in the urine as moricizine, M-sulphoxide and M-sulphone were 0.11 ± 0.09%, 0.74 ± 0.45% and 5.16 ± 4.24%, respectively. The corresponding recoveries in the bile were 0.13 ± 0.04% as moricizine, 3.39 ± 1.62% as M-sulphoxide and 2.16 ± 1.07% as M-sulphone. After an oral dose of moricizine HCl (300 mg) the plasma concentrations of moricizine, M-sulphoxide and M-sulphone at 4 h in two healthy subjects were 0.43, 0.11 and 0.10 μg/ml and 0.32, 0.17 and 0.27 μg/ml, respectively for Subject 1 and Subject 2. The percentages of dose recovered in the urine as moricizine, M-sulphoxide and M-sulphone were 0.14 and 0.02%, 0.27 and 0.36%, and 0.30 and 0.24%, respectively for Subject 1 and Subject 2. It is suggested that an investigation of the disposition of moricizine and its sulphoxidation metabolites in patients will be valuable for elucidating the prolonged effects in the treatment of ventricular arrhythmias.