Sodium salts of [[(phosphonomethyl)imino]bis[ethane-2,1-diylnitrilobis(methylene)]]tetrakisphosphonic acid (5-7 Na:1)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Indium-113m-Labeled Polyfunctional Phosphonates as Bone Imaging Agents

Author:

Subramanian G, McAfee JG, Rosenstreich M, Coco M.

Year:

1975

Bibliographic source:

J Nucl Med. 1975 Nov; 16(11):1080-4; http://jnm.snmjournals.org/content/16/11/1080.long

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

¹¹³m-In-labelled DTPMP was injected intravenously to adult albino rabbits. One to three hours after injection the rabbits were imaged in the posterior projection with a scintillation camera. Organ distribution of radiolabel was determined after the animals were sacrificed from 1 to 4 hours after injection.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

[[(phosphonomethyl)imino]bis[ethane-2,1-diylnitrilobis(methylene)]]tetrakisphosphonic acid

EC Number:

239-931-4

EC Name:

[[(phosphonomethyl)imino]bis[ethane-2,1-diylnitrilobis(methylene)]]tetrakisphosphonic acid

Cas Number:

15827-60-8

Molecular formula:

C9H28N3O15P5

IUPAC Name:

Diethylenetriaminepentakis(methylphosphonic acid)

Test material form:

not specified

Radiolabelling:

yes

Remarks:

¹¹³m-In and ⁸⁵Sr

Test animals

Species:

rabbit

Strain:

not specified

Details on species / strain selection:

Albino

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 3.5 - 5 kg
- Age at study initiation: adult

Administration / exposure

Route of administration:

intravenous

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: ¹¹³m-In or ¹¹¹In with 25-50 mg of the desired phosphonates in a volume of 4-5 ml. The pH was adjusted to 7.5-8.0 with dilute (0.1 N) sodium hydroxide or dilute (0.1 N) HCl as required since phosphonates salts dissolved in water exhibited high pH as expected and the initial pH of the mixture varied depending on the volume of the acidic indium solution. The preparation was sterilized by membrane filtration through 0.22-micron-size filters. The amount of free indium in the preparation was determined by paper electrophoresis.

Duration and frequency of treatment / exposure:

1 to 4 hours after administration

Doses / concentrations

Remarks:

Doses / Concentrations:
0.5-1 mCi of ¹¹³m-In and 2-5 mg of DTPMP

No. of animals per sex per dose / concentration:

No data

Positive control reference chemical:

10-20 µCi of ⁸⁵Sr was used as biological standard

Results and discussion

Main ADME results

Main ADME results 1

Type:

distribution

Results:

4.79 % body weight of DTPMP was distributed to average bones (Indium)

Main ADME results 2

Type:

excretion

Results:

70 % of DTPMP was excreted in the urine at 4 hours post-administration

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

The liver and soft tissue concentration of the indium complexes was lower than the ⁸⁵Sr concentration. The bone marrow concentration was low. The bone-to-blood, bone-to-marrow and bone-to-muscle ratios were comparable to those for ⁸⁵Sr.

Details on excretion:

At 4 hours post-administration, almost 70 % of DTPMP complex was excreted in the urine.

Toxicokinetic parameters

Toxicokinetic parameters:

half-life 1st: 100 min

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Table 2: Distribution of ¹⁵³Sm-labeled DTPMP

Tissue	Distribution following 4h intravenous administration (% dose/1% body weight) Subramanian (1975) (species: rabbit)
Radiolabel	85-Sr	113m-In
Blood	0.7	0.4
Plasma	Not determined	Not determined
Average bone	8.1	4.8
Marrow	0.3	0.2
Muscle	0.2	0.04
Kidney	0.9	2.3
Liver	0.3	0.2
Testes	Not determined	Not determined

Applicant's summary and conclusion

Conclusions:

The study reports that the polyfunctional phosphonate DTPMP-H selectively concentrates in the skeleton of experimental animals and has fast blood clearance.