Human moricizine metabolism. II. Quantification and pharmacokinetics of plasma and urinary metabolites

• Published in: Xenobiotica Vol. 29; no. 9; pp. 945 - 955
• Main Authors: Pieniaszek, H. J., Davidson, A. F., Chaney, J. E., Shum, L., Robinson, C. A., Mayersohn, M.
• Format: Journal Article
• Language: English
• Published: London Informa UK Ltd 01.09.1999; Taylor & Francis
• Subjects: Adult; Anti-Arrhythmia Agents - blood; Anti-Arrhythmia Agents - pharmacokinetics; Anti-Arrhythmia Agents - urine; Antiarythmic agents; Biological and medical sciences; Carbon Radioisotopes; Cardiovascular system; Half-Life; Humans; Male; Medical sciences; Middle Aged; moricizine; Moricizine - blood; Moricizine - pharmacokinetics; Moricizine - urine; Pharmacology. Drug treatments; Reference Values; Human; Healthy subject; Metabolite; Oral administration; Moracizine; Antiarrhythmic agent; Metabolism; Pharmacokinetics
• ISSN: 0049-8254; 1366-5928
• DOI: 10.1080/004982599238182

1. The metabolism of moricizine HCl was studied in 12 male volunteers dosed with 250 mg (300 μCi) 14C-radiolabelled drug. 2. Moricizine was biotransformed to many metabolites in humans (at least 35 plasma and 51 urine metabolites). 3. Urine and faecal combined mean (range) recovery accounted for 90.2% (73.4- 101.6%) of the administered radioactivity, with most of the recovered radioactivity present in faeces (mean 58.4%; range 45.6-64.7%). Mean (range) urinary recovery was 31.8% (26.2-36.9%), with <1% of the dose recovered as intact moricizine, and no one metabolite accounting for >2.5% of the dose. 4. Total radioactivity (TR) plasma t1/2 was 85.2 h, while that for moricizine was 2.4 h. Mean half-lives for plasma metabolites ranged from 2.9 to 23.6 h. The largest portion (11%) of TR AUC (area under the plasma concentration-time curve) was attributed to 2-amino-10-glucuronophenothiazine. Each of the other metabolites accounted for less of the TR AUC than parent drug except for two unidentified peaks which had comparable areas (~5% of the total radioactivity area). 5. Two identified moricizine metabolites, 2-amino-10-(3-morpholinopropionyl) phenothiazine and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate, possess the structural characteristics proposed for class 1 anti-arrhythmic activity (pendant amine functionality) and have plasma half-lives 4-7-fold longer than moricizine.