Fate of Orally Administered  Triethylenetetramine Dihydrochloride: A Therapeutic Drug for Wilson's Disease.

Kodama, Hiroko; Meguro, Yuko; Tsunakawa, Akiko; Nakazato, Yoichi; Abe, Toshiaki; Murakita, Hiroyuki

doi:10.1620/tjem.169.59

Cited by 16 publications

(19 citation statements)

References 13 publications

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“…In drug excreted via the urine, the percentage of metabolized drug was much higher in diabetic subjects (92.9 Ϯ 0.1%) than in healthy controls (77.2 Ϯ 0.2%). This is in accord with previous findings that more metabolite than parent compound is excreted in urine of humans and rats (Kobayashi et al, 1990;Kodama et al, 1993Kodama et al, , 1997Takeda et al, 1995b). The greater amount of metabolized TETA excreted in diabetic patients is consistent with the hypothesis that TETA might be more extensively metabolized in them than in healthy controls (Fig.…”

Section: Discussionsupporting

confidence: 93%

“…Most oral TETA is not absorbed, but excreted unchanged in the feces (Gibbs and Walshe, 1986). The 5 to 18% of TETA that is systemically absorbed is said to be extensively metabolized, with the majority being excreted in urine as metabolite(s) (Kodama et al, 1993(Kodama et al, , 1997, and results from rat studies have been consistent (Kobayashi et al, 1990;Takeda et al, 1995a,b,c). One major metabolite, MAT, has been reported in human urine (Kodama et al, 1997).…”

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confidence: 91%

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

Chan

Gamble

et al. 2006

Drug Metab Dispos

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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.

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Section: Discussionsupporting

confidence: 93%

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confidence: 91%

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

Chan

Gamble

et al. 2006

Drug Metab Dispos

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“…Strong acids could displace metals from TETA-metal complexes and TETA is a strong copper/zinc chelator. Therefore, strong acid was used here to release TETA from TETA-copper/zinc complexes so as to enable accurate measurement of TETA concentrations [8]. HFBA is an ion-pairing reagent used widely in chromatography, which potentially interacts with the amine groups of TETA to form a pairing-ion, thus possibly stabilizing TETA.…”

Section: Stabilitymentioning

confidence: 99%

“…However, the conductometric method has poor sensitivity [6], while the fluorescence derivatization methods using various labeling reagents all generate complex chromatograms and moreover have been optimized to detect unchanged TETA alone [7][8][9][10]. Fluorimetric methods are also associated with challenges such as: (1) whether the analyte is fully or partially labeled; (2) whether the metabolites are labeled; (3) whether the metabolites are fully or partially labeled; and (4) whether detected peaks are separated from other known or unknown metabolites.…”

Section: Introductionmentioning

confidence: 99%

Determination of triethylenetetramine (TETA) and its metabolites in human plasma and urine by liquid chromatography–mass spectrometry (LC–MS)

Chan

Poppitt

et al. 2007

Journal of Chromatography B

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“…One solution, inspired by aqueous polyamine analytic methods (18), is to use fluorescence-labeling reagents to derivatize TETA and detect its derivatives by using a fluorimetric detector. A number of fluorescence-labeling reagents have been tried, including m-toluoyl chloride, fluorescamine, dansyl chloride, O-phthalaldhyde, 4-(1-pyrene)butyric acid N-hydroxysuccinimide ester, and 9-flouorenylmehylchlorofomate (19)(20)(21)(22)(23)(24)(25). However, fluorimetric methods are associated with challenges, such as whether the analyte is fully or partially labeled, and whether detected peaks are separated from other known or unknown metabolites, polyamines, and their metabolites.…”

Section: Chemistry and Detectionmentioning

confidence: 99%

Triethylenetetramine Pharmacology and Its Clinical Applications

2010

Molecular Cancer Therapeutics

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Triethylenetetramine (TETA), a Cu II -selective chelator, is commonly used for the treatment of Wilson's disease. Recently, it has been shown that TETA can be used in the treatment of cancer because it possesses telomerase inhibiting and anti-angiogenesis properties. Although TETA has been used in the treatment of Wilson's disease for decades, a comprehensive review on TETA pharmacology does not exist. TETA is poorly absorbed with a bioavailability of 8 to 30%. It is widely distributed in tissues with relatively high concentrations measured in liver, heart, and kidney. It is mainly metabolized via acetylation, and two major acetylated metabolites exist in human serum and urine. It is mainly excreted in urine as the unchanged parent drug and two acetylated metabolites. It has a relatively short half-life (2 to 4 hours) in humans. The most recent discoveries in TETA pharmacology show that the major pharmacokinetic parameters are not associated with the acetylation phenotype of N-acetyltransferase 2, the traditionally regarded drug acetylation enzyme, and the TETA-metabolizing enzyme is actually spermidine/spermine acetyltransferase. This review also covers the current preclinical and clinical application of TETA. A much needed overview and up-to-date information on TETA pharmacology is provided for clinicians or cancer researchers who intend to embark on cancer clinical trials using TETA or its close structural analogs. Mol Cancer Ther; 9(9); 2458-67. ©2010 AACR.

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Fate of Orally Administered Triethylenetetramine Dihydrochloride: A Therapeutic Drug for Wilson's Disease.

Cited by 16 publications

References 13 publications

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

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

Determination of triethylenetetramine (TETA) and its metabolites in human plasma and urine by liquid chromatography–mass spectrometry (LC–MS)

Triethylenetetramine Pharmacology and Its Clinical Applications

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