RT Journal Article
SR Electronic
T1 Triethylenetetramine and Metabolites: Levels in Relation to Copper and Zinc Excretion in Urine of Healthy Volunteers and Type 2 Diabetic Patients
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 221
OP 227
DO 10.1124/dmd.106.012922
VO 35
IS 2
A1 Jun Lu
A1 Yi-Kai Chan
A1 Gregory D. Gamble
A1 Sally D. Poppitt
A1 Asma A. Othman
A1 Garth J. S. Cooper
YR 2007
UL http://dmd.aspetjournals.org/content/35/2/221.abstract
AB Triethylenetetramine (TETA), a selective CuII-chelator used in the treatment of Wilson's disease, is now undergoing clinical trials for the treatment of heart failure in diabetes. Despite decades of clinical use, knowledge of its pharmacology in human subjects remains incomplete. Here, we first used liquid chromatography-mass spectrometry (LC-MS) to detect and identify major metabolites of TETA in human plasma and urine, and then used this method to measure concentrations of TETA and its metabolites in the urine of healthy and diabetic subjects who were administered increasing doses (300, 600, 1200, and 2400 mg) of TETA orally. Twenty-four-hour urine collections were performed before and after dosing participants. Two major metabolites of TETA were detected in human urine, N1-acetyltriethylenetetramine (MAT) and N1,N10-diacetyltriethylenetetramine, the latter being novel. Both metabolites were verified with synthetic standards by LC-MS. The proportion of unchanged TETA excreted as a fraction of total urinary drug-derived molecules was significantly higher in healthy than in matched diabetic subjects, consistent with a higher rate of TETA metabolism in the latter. TETA-evoked increases in urinary Cu excretion in nondiabetic subjects were more closely correlated with parent drug concentrations than in diabetic subjects, whereas, by contrast, urinary Cu was more closely associated with the sum of TETA and MAT. These findings are consistent with the hypothesis that MAT could play a significant role in the molecular mechanism by which TETA extracts CuII from the systemic compartment in diabetic subjects. The American Society for Pharmacology and Experimental Therapeutics