Pharmacokinetics, Pharmacodynamics, and Metabolism of Triethylenetetramine in Healthy Human Participants: An Open-Label Trial

J Clin Pharmacol. 2010 Jun;50(6):647-58. doi: 10.1177/0091270009349379. Epub 2010 Feb 9.

Abstract

The selective Cu(II)-chelator, triethylenetetramine (TETA), is undergoing clinical trials for the treatment of heart failure in patients with diabetes. Recently, the authors showed that 2 acetylated metabolites, N(1)-acetyltriethylenetetramine (MAT) and N(1),N(10)-diacetyltriethylenetetramine (DAT), are formed in humans following oral TETA administration. Thus, it became necessary to determine whether the N-acetyltransferase (NAT) 2 phenotype has any effects on the pharmacological properties and safety profile of TETA. Twelve fast and 12 slow NAT2-phenotype healthy participants were recruited. After oral drug administration, the authors collected plasma and urine samples, measured plasma concentrations of TETA and its 2 metabolites along with concomitant urinary copper concentrations, and performed safety tests. They present, for the first time, the complete 24-hour pharmacokinetic profiles of TETA, MAT, and DAT in humans. There was no evidence for clear-cut differences in pharmacokinetic profiles between fast and slow acetylators. Pharmacodynamic analysis showed no significant differences in cupruresis between the 2 NAT2 phenotypes. Safety results were consistent with TETA being well tolerated, and no significant differences in safety profiles were observed between the 2 phenotypes. Based on these data, NAT2 phenotype does not affect TETA's pharmacokinetic, pharmacodynamic, or safety profiles. TETA may be acetylated via an alternative mechanism, such as that catalyzed by spermidine/spermine N(1)-acetyltranferase.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Arylamine N-Acetyltransferase / genetics
  • Chelating Agents / adverse effects
  • Chelating Agents / pharmacokinetics*
  • Chelating Agents / pharmacology*
  • Copper / urine
  • Female
  • Humans
  • Male
  • Middle Aged
  • Phenotype
  • Time Factors
  • Trientine / adverse effects
  • Trientine / analogs & derivatives
  • Trientine / blood
  • Trientine / metabolism*
  • Trientine / pharmacokinetics*
  • Trientine / pharmacology*

Substances

  • Chelating Agents
  • N1,N10-diacetyltriethylenetetramine
  • N1-acetyltriethylenetetramine
  • Copper
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human
  • Trientine