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 microCi) 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 2amino-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 (approximately 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.
Pieniaszek
H J
HJ
Drug Metabolism and Pharmacokinetics Section, DuPont Pharmaceuticals Company, Stine-Haskell Research Center, Newark, DE 19714, USA. henry.j.pieniaszek@dupontpharma.com
Davidson
A F
AF
Chaney
J E
JE
Shum
L
L
Robinson
C A
CA
Mayersohn
M
M
D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000652:urine*; D002250:Carbon Radioisotopes; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D016293:Moricizine / Q000097:blood* / Q000493:pharmacokinetics / Q000652:urine*; D012016:Reference Values
D000889:Anti-Arrhythmia Agents; D002250:Carbon Radioisotopes; D016293:Moricizine