Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Carbon-11 labeled aliphatic amines in lung uptake and metabolism studies: potential for dynamic measurements in vivo
Author:
Fowler JS et al.
Year:
1976
Bibliographic source:
J Pharmacol Exp Ther 198 (1), 133-145

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
A series of aliphatic amines (C4-C10 and C13) labeled with carbon-11 (T 1/2 = 20.4 minutes) has been used as a model for studying some basic parameters affecting amine uptake and metabolism by the lung and other tissues in mice after iv injection.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Carbon-11-labeled primary alkylamines, varying in carbon chain
length from C4 to C10, and C13
- Purity unknown
Radiolabelling:
yes
Remarks:
carbon-11

Test animals

Species:
mouse
Strain:
other: Swiss albino mice, BNL strain
Details on test animals and environmental conditions:
No details

Administration / exposure

Route of administration:
intravenous
Vehicle:
unchanged (no vehicle)
Doses / concentrations
Remarks:
Doses / Concentrations:
0.5 to 5.0 X 10E-10 mol/mouse (0.1-1 mCi/mouse)

Results and discussion

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

The lung uptake (percentage of dose per organ) of aliphatic amines at 1 minute increased from 2.18 +/- 0.13% for butylamine to 13.33 +/- 0.84% for tridecylamine. Partition coefficients (between n-octanol and pH = 7 buffer) were measured for the C4 through C10 amines and for octanoic acid and octanenitrile. Within the amine series, the partition coefficient correlated with lung uptake. A comparison of a series of compounds all having a carbon chain length of eight but with different functional groups (--NH2, --C=N, --CO2H, --OH) showed that the amino group as well as the relatively lipophilic alkyl group were required for lung specificity. The 11C-aliphatic amines were rapidly metabolized via monoamine oxidase (ultimately to 11CO2). Non-amine metabolites in blood and lungs at 5 minutes postinjection were 95 and 50%, respectively. Pretreatment of mice with iproniazid and with pargyline decreased 11CO2 excretion, and iproniazid significantly increased the radioactivity retained by the brain, lungs and liver at 15 minutes.

Tridecylamine had the longest carbon chain of the tested series of amines. Liberation of carbon dioxide from injected Tridecylamine was relatively slow. It was only ca. 14 % of the injected dose at 20 min post injection. At the same time point CO2-excretion of the alkyl amines C4 to C10 amounted to more than 40 % of the dose, and exceeded 50 % in the case of C6 and C7 alkylamines. Pretreatment with inhibitors of Monoamine Oxidases (MAO) significantly increased the radioactivity retained by the brain, lungs, and liver (after injection of 11C-n-octylamine). The rate of CO2-excretion depended on the carbon chain length in the order C4<C5<C6>C7>C8>C9>C10>C13.

Applicant's summary and conclusion