Triethylenetetramine and Metabolites: Levels in Relation to Copper and Zinc Excretion in Urine of Healthy Volunteers and Type 2 Diabetic Patients

Abstract

ABSTRACT:Triethylenetetramine (TETA), a selective Cu II -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 chromatographymass 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, N 1 -acetyltriethylenetetramine (MAT) and N 1 ,N 10 -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 Cu II from the systemic compartment in diabetic subjects.

Triethylenetetramine Pharmacology and Its Clinical Applications

“…Metabolite(s) recovery ranges from 2.50 to 9.00% in healthy volunteers; and, from 8.56 to 27.1% in patients with diabetes or Wilson's disease (Table 2). It is suggested that patients with diabetes have a higher rate of TETA metabolism than healthy volunteers (38). Whether other disease states, such as Wilson's disease or cancer, have the same effect on TETA metabolism as diabetes has not been established, but further investigation is warranted.…”

“…Patients affected with diabetes excrete more metabolites in urine than healthy volunteers (38). It has been reported that urinary excretion of spermine is elevated in patients with certain types of cancer (50,51).…”

“…Most of the urinary excreted TETA is in the form of the unchanged parent compound and two acetylated metabolites, MAT and DAT (38). Patients affected with diabetes excrete more metabolites in urine than healthy volunteers (38).…”

“…MAT was first identified in 1993 (36), and further studied in 1997 (37). DAT was first identified in 2007 (27), and further studied together with MAT in both healthy volunteers and patients affected with diabetes (38,40).…”

“…Clinical results were obtained from healthy volunteers (22,23,(35)(36)(37)(38)(39)(40), patients presenting with Wilson's disease (20,31,41), and type 2 diabetes patients (38). Detailed pharmacokinetic parameters listed in Tables 1 and 2 are discussed in relation to absorption, distribution, metabolism, and excretion in the next four sections.…”