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

1. The metabolism of moricizine HCl was studied in 12 male volunteers dosed with 250 mg (300 mu Ci) C-14-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 r adioactivity present in faeces (mean 58.4 %; range 45.6-64.7 %). Mean (rang e) urinary recovery was 31.8 % (26.2-36.9 %), with < 1 % of the dose recove red as intact moricizine, and no one metabolite accounting for > 2.5 % of t he dose. 4. Total radioactivity (TR) plasma t(1/2) was 85.2 h, while that for morici zine was 2.4 h. Mean half-lives for plasma metabolites ranged from 2.9 to 2 3.6 h. The largest portion (11 %) of TR AUC (area under the plasma concentr ation-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 (similar to 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] carbama te, possess the structural characteristics proposed for class 1 anti-arrhyt hmic activity (pendant amine functionality) and have plasma half-lives 4-7- fold longer than moricizine.