[Disposition behavior and absorption mechanism of trientine, an orphan drug for Wilson's disease].
The disposition behavior of trientine, a selective copper-chelating drug for Wilson's disease, and its metabolites in normal patients with Wilson's disease and rats were studied. A high concentration of metabolites appeared in blood samples of patients and rats in the early stage after administration of trientine. Furthermore, large amount of trientine metabolites were excreted into the urine of patients. These results suggest that trientine is remarkably subjected to a first-pass effect. The drug concentration area under the curve (AUC) of the unchanged form and the metabolites of trientine in patients was not dependent on the administered dosage. It seems that the absorption process is an important factor for the disposition behavior of trientine, we have also investigated the uptake characteristics of trientine by rat intestinal brush-border membrane vesicles. The uptake characteristics of trientine were similar to the physiological polyamines, spermine and spermidine. The uptake rate of trientine was dose-dependently inhibited by spermine and spermidine. Moreover, spermine competitively inhibited the uptake of trientine with a Ki value of 18.6 muM. This value is very close to the Km value for spermine (30.4 muM). These data suggested that the uptake mechanism of trientine in rat small intestinal brush-border membrane vesicles was almost identical to that of spermine and spermidine, and that the physiological polyamines seem to have the ability to inhibit the absorption of trientine from the gastrointestinal tract.
Tanabe
R
R
Department of Pharmacy, Hokkaido University Hospital, Hokkaido University School of Medicine, Sapporo, Japan.
D000818:Animals; D015317:Biogenic Polyamines / Q000493:pharmacokinetics; D002614:Chelating Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D005260:Female; D006527:Hepatolenticular Degeneration / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008871:Microvilli / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014266:Trientine / Q000493:pharmacokinetics* / Q000627:therapeutic use
D015317:Biogenic Polyamines; D002614:Chelating Agents; D014266:Trientine