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

Abstract

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.

Functional analysis of phenolsulfonphthalein transport system in Long–Evans Cinnamon rats

“…A previous study has revealed that LEC rats have not only impaired canalicular transport of BSP but also impaired urinary excretion of PSP [13]. However, urinary nitrogen and creatinine did not show serious renal failure [14]. These results suggest that the function of the renal secretion system for PSP in LEC rats is impaired.…”

Triethylenetetramine Pharmacology and Its Clinical Applications

“…One early study reported that LEC rats, a rat model of Wilson's disease, had significantly lower urinary TETA excretion than that in normal Wistar rats. This lower rate wasdue to the impairment of kidney function in LEC rats (29).…”

“…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.…”

“…The intestinal absorption rate in normal male Wistar rats has been reported to be 42% in the jejunum and 22.5% in the ileum using an in situ loop method (30). In Long-Evans Cinnamon (LEC) rats, the model organism for Wilson's disease, the jejunum absorption rate has been reported to be approximately 46%, and without statistical significance when compared with data derived from Wistar rats (29). In Sprague Dawley rats, the extent of absorption after oral TETA administration has been reported to be 44.3% (34).…”

“…In vitro experiments have shown that about 50% of TETA was eliminated from the S9 liver fraction system after 2 hours of incubation (29). One in vivo study in rats showed that after oral administration of trientine, only 3.1% of the dose was found in the 24-hour urine collection as the unchanged parent compound, whereas metabolites accounted for 32.6% of the oral dose (30).…”