Abstract
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.
Footnotes
-
This study was funded by grants from the Foundation for Research Science and Technology, New Zealand. the Health Research Council of New Zealand, and by Protemix Corporation.
-
G.G. is a consultant to, J.L., S.P., and A.A.O. are employed by, and G.C. is a Shareholder and Director of Protemix.
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
doi:10.1124/dmd.106.012922.
-
ABBREVIATIONS: TETA, triethylenetetramine; ACS, N1-acetylspermine; ADME, absorption, distribution, metabolism, and excretion; DAT, N1,N10-diacetyltriethylenetetramine; HFBA, heptafluorobutyric acid; HPLC, high-pressure liquid chromatography; LC-MS, liquid chromatography-mass spectrometry; MAT, N1-acetyltriethylenetetramine; NAT, N-acetyltransferase; PABA, p-aminobenzoic acid; ICPMS, inductively coupled plasma mass spectrometry; HFBA, heptafluorobutyric acid; SIM, selected-ion monitoring; LME, linear mixed-effects model; LLOQ, lower limit of quantification.
- Received September 14, 2006.
- Accepted November 8, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|