Trientine

Endpoint summary

Additional information

Studies using 14-carbon labelled trientine (TETA) given to rats indicate that only some 20% of the drug is absorbed from the gut. It was detected in all tissues analysed, with a maximum concentration in the kidneys. It is rapidly excreted in the urine and more slowly in the bile. There is no evidence that the compound is broken down in the body, but biotransformation does occur, probably by acetylation and possibly other forms of conjugation. The conjugates can all be converted back to trientine by acid hydrolysis (Gibbs, 1986).

A study on dermal absorption concluded that " Triethylenetetraamine is not absorbed through the skin to any appreciable extent" (Oyen, 1953).

Another study, on carcinogenicity (DePass 1987), states "Although no skin penetration studies were performed with these ethyleneamines, such studies were performed in the rat with EDA. The results indicated that the rate of absorption was concentration dependent and relatively slow following topical application (Yang et al.,1983a). The estimated absorption was 55 and 12% respectively, when 25 and 10% aqueous solutions were applied for 24 hr. Because of the higher weights and greater number of potentially positively charged amino groups of these ethyleneamines compared to EDA, it is likely that there was very limited systemic circulation of the compounds in these studies. This would be consistent with the absence of systemic toxic effects”

It is therefore concluded that TETA is poorly absorbed after oral administration and very poorly, if at all, absorbed after dermal application. If absorbed, it is rapidly metabolized and excreted.

Other studies were done with TETA.2HCl (CAS 38260 -01 -4). The 8 -h TETA excretion by 2 subjects was only 1.6 and 1.7%, respectively, of the administered dose. This finding apparently suggested that TETA was hardly absorbed through the digestive tract (Kodoma 1993). This was supported by Kobayashi (1990) showing that the bioavailability of TETA was below 10% and the plasma levels of TETA in non-fasted rats were significantly lower than that observed in fasted rats. The urinary excretion of unchanged TETA during 24 h was only 3.5% of the orally administered dose. However, the urinary excretion of total TETA including metabolites, though they have not been identified, was 35.7%. These results suggest that low bioavailability of TETA might be due to the rapid metabolism in the body after absorption from the gastrointestinal tract. Bioavailability of 25.5% in rats in a fasting state and 14.0% in rats not in a fasting state was also reported (Takeda 1995). The main absorption route for TETA might be permeation across the plasma membrane of intestinal epithelial cells, brush border membrane (BBM) of rat small intestine (Kobayashi 1990). The concentration of dosage solution and first pass metabolism in the intestinal wall may play an important role in the absorption of TETA in humans as well as in rats (Takeda 1995). Tanabe (1996a) showed that the predominant transport process of polyamines in rat intestinal brush-border membrane seemed to be passive diffusion which is dependent on the electrostatic binding to the acidic phospholipids such as phosphatidylserine. The uptake of TETA by rat intestinal brush-border membrane vesicle shares with polyamine a common transport mechanism which includes a charge-interaction between the polycation and the negative charge of the inner membrane layer. This mechanism provides an explanation for the poor and variable absorption of TETA. A study with beagle dogs showed that no significant accumulation of TETA occurred during the dosing period (Meamura 1998).