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

H. J. Pieniaszek, A. F. Davidson, J. E. Chaney, L. Shum, C. A. Robinson, Michael Mayersohn

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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 t(1/2) 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.

Original languageEnglish (US)
Pages (from-to)945-955
Number of pages11
JournalXenobiotica
Volume29
Issue number9
DOIs
StatePublished - 1999

Fingerprint

Moricizine
Pharmacokinetics
Radioactivity
Metabolites
Metabolism
Plasmas
Area Under Curve
Urine
Recovery
Carbamates
Anti-Arrhythmia Agents
Feces
Pharmaceutical Preparations
Dosimetry
Amines
Volunteers
Parents

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Pharmacology
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Human moricizine metabolism. II. Quantification and pharmacokinetics of plasma and urinary metabolites. / Pieniaszek, H. J.; Davidson, A. F.; Chaney, J. E.; Shum, L.; Robinson, C. A.; Mayersohn, Michael.

In: Xenobiotica, Vol. 29, No. 9, 1999, p. 945-955.

Research output: Contribution to journalArticle

Pieniaszek, H. J. ; Davidson, A. F. ; Chaney, J. E. ; Shum, L. ; Robinson, C. A. ; Mayersohn, Michael. / Human moricizine metabolism. II. Quantification and pharmacokinetics of plasma and urinary metabolites. In: Xenobiotica. 1999 ; Vol. 29, No. 9. pp. 945-955.
@article{bad2d77969ac41e3aab4a87694606f82,
title = "Human moricizine metabolism. II. Quantification and pharmacokinetics of plasma and urinary metabolites",
abstract = "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 t(1/2) 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.",
author = "Pieniaszek, {H. J.} and Davidson, {A. F.} and Chaney, {J. E.} and L. Shum and Robinson, {C. A.} and Michael Mayersohn",
year = "1999",
doi = "10.1080/004982599238182",
language = "English (US)",
volume = "29",
pages = "945--955",
journal = "Xenobiotica",
issn = "0049-8254",
publisher = "Informa Healthcare",
number = "9",

}

TY - JOUR

T1 - Human moricizine metabolism. II. Quantification and pharmacokinetics of plasma and urinary metabolites

AU - Pieniaszek, H. J.

AU - Davidson, A. F.

AU - Chaney, J. E.

AU - Shum, L.

AU - Robinson, C. A.

AU - Mayersohn, Michael

PY - 1999

Y1 - 1999

N2 - 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 t(1/2) 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.

AB - 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 t(1/2) 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.

UR - http://www.scopus.com/inward/record.url?scp=0032830061&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032830061&partnerID=8YFLogxK

U2 - 10.1080/004982599238182

DO - 10.1080/004982599238182

M3 - Article

VL - 29

SP - 945

EP - 955

JO - Xenobiotica

JF - Xenobiotica

SN - 0049-8254

IS - 9

ER -