Sodium salts of [[(phosphonomethyl)imino]bis[ethane-2,1-diylnitrilobis(methylene)]]tetrakisphosphonic acid (1-3 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:

Skeletal Localization of Samarium-153 Chelates: Potential Therapeutic Bone Agents

Author:

Goeckeler WF, Edwards B, Volkert WA, Holmes RA, Simon J, Wilson D. J.

Year:

1987

Bibliographic source:

Nucl Med. 1987 Apr; 28(4):495-504

Materials and methods

Objective of study:

absorption

distribution

excretion

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

¹⁵³Sm-labelled DTPMP was injected into the tail vein of male rats. Two hours after injection the animals were sacrificed and tissues were obtained for analysis.

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:

¹⁵³Sm

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Weight at study initiation: 160-220 g

- Housing: each rat was housed individually in a cage for 2 hours

Administration / exposure

Route of administration:

intravenous

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Sm₂O₃ was obtained as 99.06 % enriched ¹⁵²Sm. The ¹⁵³Sm was prepared by neutron irradiation using a thermal flux of 8.5 x 10¹³ n/cm² sec and a resonance flux of 1.7 x 10¹² n/cm² sec. A weighed amount of Sm₂O₃ was flame scaled into a quartz vial under vacuum and welded into aluminium can. Following irradiation the sample was opened, dissolved in 1-4 N HCl and brought to a stock concentration of approximately 1.2 x 10⁻³ M with deionized water. To form each ¹⁵³Sm complex 25-80 mg/ml of ligand were used. The amount of ligand used to achieve quantitative complex formation was first dissolved in deionized water followed by the addition of concentrated base. The ¹⁵³Sm stock and carrier solutions were added and the final samarium concentration was 3x 10⁻⁴ M with a specific activity of 1 to 10 mCi/ml (37-370 MBq/ml). The pH was adjusted to >10 and the solution heated to 60 °C for 30 min to facilitate complexation. After heating the pH was adjusted to 7.0 with 4-5M HCl.

50-100 microliters of the ligand complex were injected into the tail veins of unanaesthetised rats. The rats were exposed to the substance for 2 hours and were then sacrificed.

Duration and frequency of treatment / exposure:

2 hours

Doses / concentrations

Remarks:

1.2 x 10⁻³ M with deionized water.
50-100 µL were administered to the animals.

No. of animals per sex per dose / concentration:

No data

Control animals:

not specified

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, blood 1ml , plasma, femur, cage washes, bile
- Time and frequency of sampling: at 2 hours post injection
- The samples were counted using an inverted Nal(T1) thyroid detector

Results and discussion

Main ADME results

Main ADME results 1

Type:

distribution

Results:

30 % of ¹⁵³Sm-labelled DTPMP was distributed to the average bone tissue

Main ADME results 2

Type:

excretion

Results:

70 % of ¹⁵³Sm-labelled DTPMP was excreted in the urine

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

30 % skeletal uptake was observed following injection of Samarium-153 DTPMP. Moderate skeletal uptake of the test substance.

Details on excretion:

Over 70% of Samarium-153 DTPMP was excreted in the urine. It clears from blood and other soft tissues.

Toxicokinetic parameters

Toxicokinetic parameters:

half-life 1st: Samarium-153 46.8 h

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Table 1: Distribution of ¹⁵³Sm-labeled DTPMP

Tissue	Distribution following 2h intravenous administration (% dose/g) (2h) Goeckeler (1987) (species: rat)
Radiolabel	153-Sm
Blood	74
Plasma	Not determined
Average bone	30
Marrow	Not determined
Muscle	0.9
Kidney	0.4
Liver	0.3
Testes	Not determined

Applicant's summary and conclusion

Conclusions:

The study reports that DTPMP (neutralised; administered by intravenous injection) is moderately distributed to skeletal tissue and rapidly cleared from blood and soft tissues into urine (70% within two hours of injection).