Pharmacokinetics, pharmacodynamics, and metabolism of triethylenetetramine in healthy human participants: an open-label trial.
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.
Lu
Jun
J
School of Biological Sciences, Faculty of Science, University of Auckland, Auckland 1142, New Zealand.
Poppitt
Sally D
SD
Othman
Asma A
AA
Sunderland
Tracey
T
Ruggiero
Katya
K
Willett
Michael S
MS
Diamond
Lisa E
LE
Garcia
Wilfredo D
WD
Roesch
Benno G
BG
Cooper
Garth J S
GJ
D000328:Adult; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D002614:Chelating Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003300:Copper / Q000652:urine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D013997:Time Factors; D014266:Trientine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology*
D002614:Chelating Agents; C525989:N1,N10-diacetyltriethylenetetramine; C525988:N1-acetyltriethylenetetramine; D003300:Copper; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D014266:Trientine