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Pharmacokinetics, Pharmacodynamics, and Metabolism of Triethylenetetramine in Healthy Human Participants: An Open‐Label Trial
Author(s) -
Lu Jun,
Poppitt Sally D.,
Othman Asma A.,
Sunderland Tracey,
Ruggiero Katya,
Willett Michael S.,
Diamond Lisa E.,
Garcia Wilfredo D.,
Roesch Benno G.,
Cooper Garth J. S.
Publication year - 2010
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270009349379
Subject(s) - pharmacokinetics , triethylenetetramine , pharmacodynamics , pharmacology , cmax , medicine , oral administration , chemistry , organic chemistry
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 .