Determination of triethylenetetramine in plasma of patients by high-performance liquid chromatography.

Miyazaki, Katsumi; Kishino, Satoshi; Kobayashi, Mariko; Arashima, Shinichiro; Matsumoto, Shuzo; Arita, Takaichi

doi:10.1248/cpb.38.1035

Cited by 17 publications

(15 citation statements)

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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%

“…Most preclinical studies were done on rats (20,(28)(29)(30)(31)(32)(33)(34); only one study on dogs (21) and one study on rabbits (22) have been reported. Early studies used 14 C-labeled TETA hydrochloride salts.…”

Section: Summary Of Pharmacokinetic Parameters In Preclinical and CLImentioning

confidence: 99%

“…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.…”

Section: Summary Of Pharmacokinetic Parameters In Preclinical and CLImentioning

confidence: 99%

“…One study reported a bioavailability of 2.31% in nonfasted rats and 6.56% in fasted rats (30). A second report showed bioavailability in three fasted rats at 5.6%, 5.7%, and 16.4%, respectively (20). A third report provided a bioavailability of 14.0% in nonfasted rats and 25.5% in fasted rats (32).…”

Section: Absorption In Animalsmentioning

confidence: 99%

“…The T max values from various studies occur between 0.8 to 4 hours (Table 2), indicating overall slow absorption. There seems to be a large variance of C max (0.4 to 20 mg/L) among different individuals with Wilson's disease who had been dosed with 600 mg trientine in one early study (20). However, the C max variance seems to be less profound in healthy volunteers on the same dose, that is, 0.80 ± 0.33 mg/L (mean ± SD) in one recent study (40), and 0.69 ± 0.41 mg/L in another recent report (39).…”

Section: Absorption In Humansmentioning

confidence: 99%

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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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Section: Chemistry and Detectionmentioning

confidence: 99%

Section: Summary Of Pharmacokinetic Parameters In Preclinical and CLImentioning

confidence: 99%

Section: Summary Of Pharmacokinetic Parameters In Preclinical and CLImentioning

confidence: 99%

Section: Absorption In Animalsmentioning

confidence: 99%

Section: Absorption In Humansmentioning

confidence: 99%

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Triethylenetetramine Pharmacology and Its Clinical Applications

2010

Molecular Cancer Therapeutics

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Comparison of disposition behavior and de‐coppering effect of triethylenetetramine in animal model for Wilson's disease (long‐evans cinnamon rat) with normal Wistar rat

Iseki

Kobayashi

Ohba

et al. 1992

Biopharm & Drug Disp

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The disposition behaviors and de-coppering effect of triethylenetetramine dihydrochloride (trientine), a selective chelating agent for copper and an 'orphan drug' for Wilson's disease, have been evaluated in an animal model, Long-Evans Cinnamon (LEC) rats, and normal rats (Wistar). In LEC rats, urinary excretion of trientine was remarkably lower than that of Wistar rats. The absorption rates from the jejunal loop and in vitro metabolism in the liver S9 fraction (supernatant of 9000 x g) were approximately the same for both strains. The decline of urinary excretion of trientine in LEC rats is thought to be due mainly to the lowering of the functional activity of the kidney, because urinary excretion of creatinine and phenolsulfonphthalein were significantly lower in LEC rats than those in Wistar rats. Both acceleration of urinary excretion of copper and reduction of hepatic copper levels were observed with treatment of trientine in LEC rats aged 6 weeks. In LEC rats aged 13 weeks, however, no de-coppering effect from the liver was observed, though urinary excretion of copper was increased. These results suggest that trientine has a pharmacological effect in disease state, especially in the early stages of hepatitis.

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The copper chelator trientine has an antiangiogenic effect against hepatocellular carcinoma, possibly through inhibition of interleukin‐8 production

Moriguchi

Nakajima

Kimura

et al. 2002

Intl Journal of Cancer

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Recent studies have revealed that copper is an important cofactor for several angiogenic agents. We examined the antiangiogenic effect against hepatocellular carcinoma (HCC) of the copper chelator trientine, especially focusing on the relationship between copper and interleukin-8 (IL-8), a potent angiogenic factor produced by hepatoma cells. HuH-7 hepatoma cells were transplanted into nude mice and the growth of xenograft tumors was compared to and without administration of trientine. Using the resected tumor, microvessel density, apoptotic potential and proliferative activity were analyzed histologically and IL-8 mRNA was semiquantified by RT-PCR. In addition, HuH-7 cells were cultured in control medium, medium supplemented with copper, medium supplemented with trientine and medium supplemented with both copper and trientine. Human IL-8 levels were measured in the supernatants by ELISA. Using the extracts from cultured cells, IL-8 mRNA was semiquantified by RT-PCR. Trientine suppressed the growth of xenograft tumors significantly. Histologically, apoptotic potential was increased significantly and microvessel density, decreased. The production of IL-8 from the tumor was suppressed by trientine. In vitro, IL-8 production by HuH-7 cells in coppercontaining medium was significantly greater than that in copper-free medium, and this effect was weakened when trientine was added. However, no significant change was apparent when trientine was added to the medium alone. In conclusion, the chelating effect of trientine prevented copper from functioning as a cofactor in angiogenesis, which resulted in reduced IL-8 production from HuH-7 cells.

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Determination of triethylenetetramine in plasma of patients by high-performance liquid chromatography.

Cited by 17 publications

References 0 publications

Triethylenetetramine Pharmacology and Its Clinical Applications

Triethylenetetramine Pharmacology and Its Clinical Applications

Comparison of disposition behavior and de‐coppering effect of triethylenetetramine in animal model for Wilson's disease (long‐evans cinnamon rat) with normal Wistar rat

The copper chelator trientine has an antiangiogenic effect against hepatocellular carcinoma, possibly through inhibition of interleukin‐8 production

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