Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tract and metabolism products, ATC-Code: A16AX12 
Mechanism of action
Trientine is a copper-selective chelator that enhances systemic elimination of divalent copper by forming a stable complex that is readily excreted by the kidneys.
Trientine is a chelator with a polyamine-like structure and copper is chelated by forming a stable complex with the four constituent nitrogens in a planar ring. Thus, the pharmacodynamic action of trientine is dependent on its chemical property of chelating copper and not on its interaction with receptors, enzyme systems or any other biological system that might differ between species. Trientine may also chelate copper in the intestinal tract and so inhibit copper absorption.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
Following oral administration at a single dose of 167 mg trientine base (250 mg trientine dihydrochloride salt) of Trientine RAZ 250mg in healthy subjects, trientine was rapidly absorbed with median Tmax values of 1.25 hours. The Cmax was 933.99 ± 345.99 ng/mL and AUC0-t 3771.15 ± 1962.20 hr.ng/mL.

Food intake inhibits absorption shown by reduced Cmax and decreased area under the curve, AUC. Thus, trientine is to be given on empty stomach at least one hour before meals or 2 hours after meals.
Distribution
The central and peripheral volumes of distribution are 393 L and 252 L, respectively, which indicates that trientine is widely distributed in the human body, where accumulation in certain tissues is likely to happen.

Biotransformation
Trientine is acetylated in two major metabolites, N1-acetyltriethylenetetramine (MAT) and N1,N10-diacetyltriethylenetetramine (DAT). Clinical data in healthy subjects indicate that the plasma exposure to the MAT metabolite is approximately 3 times that of unchanged trientine, while exposure to the DAT metabolite is slightly lower compared to trientine. The metabolites of trientine have Cu-chelating properties, however the stability of these Cu-complexes is low due to the introduction of the acetyl groups. Clinical data in healthy volunteers suggest limited contribution of chelating activity by the MAT and DAT metabolites. The extent of MAT and DAT's contribution to the overall effect of trientine on copper levels in Wilson's Disease patients remains to be determined.

Trientine is metabolised by acetylation via spermidine/spermine N- acetyltransferase and not via N-acetyltransferase 2.

Elimination
After absorption, trientine and its metabolites are rapidly excreted in the urine, either bound to copper or unbound. The unabsorbed fraction of orally administered trientine is bound to intestinal copper and eliminated through faecal excretion.

The elimination half-life of trientine is approximately 4 hours (mean t1/2 of 3.8 ± 1.3 hours measured at steady state in WD patients and 4.4 ± 4.7 hours measured after a single dose in healthy volunteers). The elimination half-lives of the two metabolites were 14.1 ± 3.7 hours for MAT and 8.5 ± 3.0 hours for DAT after a single dose administration of trientine in healthy subjects.