Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1986
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Not performed according to guideline or GLP, limited details on methods and results. No information on test substance composition or purity.

Data source

Reference
Reference Type:
other: proceedings of colloquia
Title:
The metabolism of trientine: animal studies
Author:
Gibbs, K.R., Walshe, J. M.
Year:
1986
Bibliographic source:
Orphan diseases and orphan drugs. - (Fulbright papers; v. 3) I. Chemotherapy. 2. Orphan drugs. I. Scheinberg, Herbert. 11. Walshe, J. M.111. Series. ISBN 0-7190-2295-9 hardback.

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid
Details on test material:
14C labelled triethylene tetramine 4HCI/MW 292. Prepared by the Radiochemical Centre, Amersham, and was shown by their analysis to be 96% pure. The specific activity was 26 pCi/mg (926 kBq/mg).
No further details.
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
other: Norwegian hooded
Sex:
not specified

Administration / exposure

Route of administration:
other: oral, iv
Vehicle:
not specified
Duration and frequency of treatment / exposure:
Labelled trientine was administered orally to fourteen rats, after an overnight fast.
Eight rats were given the drug by the intravenous (tail vein) route.
Doses / concentrations
Remarks:
Doses / Concentrations:
oral
26 µCi (12 animals) and 100 µCi (2 animals)

iv
2 to 4 µCi
No. of animals per sex per dose:
no data
Control animals:
no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
After oral administration the percentage absorbed, that is, the 14C detected in carcass and urine, was between 6% and 18%, the partition varying between almost entirely carcass activity at one hour to almost entirely urine activity at seventy-two hours. The maximum recovery in the urine in any single study was 15 %. No test substance was exhaled.
After iv administration between 50% and 60% of the labelled test substance was excreted in the urine within 6 hours. 20% was found in the feaces after 48 hours.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
In the small gut at least 6 radio active compounds were present. In the plasma filtrate two new bands were found. Both moved slower than the parent compound and one was equal in concentration to the parent compound. The same was observed after incubation of liver and kidney mince with the test compound. Multiple bands of radioactivity were found in urine, with very little of the parent compound remaining but with a rather strong diffuse band moving at approximately half the speed of trientine. This compound has not been found in plasma, liver or kidney preparations.
The observation that the various derivatives of trientine found in urine can be converted back to the parent compound, simply by hydrolysis, strongly suggested that these were conjugates or chelates of trientine.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
The compound is poorly abosorbed after oral and iv administration, rapidly conjugated and excreted.
Executive summary:

Studies using 14carbon labelled trientine 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.