Dilanthanum tricarbonate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication which meets basic scientific principles

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Systemic lanthanum is excreted in the bile of rats

Author:

Damment, S.J.P. and Pennick, M.

Year:

2007

Bibliographic source:

Toxicology Letters 171: 69-77

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Following single oral gavage the plasma lanthanum concentration was determined in rats at different time intervalls.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Dilanthanum tricarbonate

EC Number:

209-599-5

EC Name:

Dilanthanum tricarbonate

Cas Number:

587-26-8

Molecular formula:

La2(CO3)3

IUPAC Name:

dilanthanum tricarbonate

Details on test material:

- Name of test material (as cited in study report): Lanthan carbonate
- Molecular formula (if other than submission substance): [La2(CO3)3·4H2O]
- Analytical purity: no data

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River UK Ltd. (Margate, UK) or Harlan UK Ltd. (Bicester, UK).
- Weight at study initiation: 165-253 g

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Lanthanum carbonate was suspended in 0.5% (w/v) carboxymethyl cellulose for oral administration.

Duration and frequency of treatment / exposure:

single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
1500 mg/kg (765 mg/kg elemental lanthanum)

No. of animals per sex per dose / concentration:

3 animals per sex, per time point

Control animals:

yes, concurrent vehicle

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, plasma
- Time and frequency of sampling: pre-dose, and at 1, 2, 4, 8, 12, 24, 48 and 72 h after administration

PREPARATION OF BLOOD/PLASMA
- Blood was centrifuged and plasma separated and diluted with tetramethyl ammonium hydroxide (TMAH) solution (1.25% [w/v] containing 0.1% [w/v] ethylenediaminetetraacetic acid diammonium salt [EDTA (NH4)2] as a lanthanum chelator). Lanthanum content was determined using an Agilent (Hewlett Packard) 4500 inductively coupled plasma (ICP)-mass spectrometer fitted with a Babington V-groove nebulizer and a glass spray chamber (Scott double pass cooled to 2 °C).
- The lower limit of quantification was 0.05 ng/mL.

Statistics:

Pharmacokinetic parameters were derived from plasma lanthanum concentrations by visual inspection of the individual or mean plasma concentration curves or by non-compartmental analysis using WinNonlin® (Version 3.0, Pharsight Corporation, Mountain View, California).
The observed maximum plasma lanthanum concentration (Cmax) and the time post-dose at which Cmax occurred (Tmax) were determined by visual inspection of individual or mean plasma concentration versus time curves. The area under the plasma concentration versus time curves, calculated from time 0 to 24 h post-dose (AUC0–24), and from time 0 to the last sample collection time (AUClast) were calculated using linear trapezoidal summation from time 0 to the appropriate time point.
The absolute bioavailability (percentage of the administered oral dose absorbed) was calculated from the equation, F = (AUC 0–24PO/Dose PO)/(AUC0–24 IV/Dose IV)×100.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

After a 1500 mg/kg oral dose of lanthanum carbonate Cmax was 1.04±0.31 ng/mL with a Tmax of 8 h. Thereafter, plasma lanthanum levels decreased to 0.11±0.04 ng/mL at 72 h.
Calculation of absolute oral bioavailablity: 0.0007%

Toxicokinetic parameters

Toxicokinetic parameters 1

Test no.:

#1

Toxicokinetic parameters:

Cmax: 1.04+/-0.31 ng/mL

Toxicokinetic parameters 2

Test no.:

#1

Toxicokinetic parameters:

AUC: 0-24 h: 15.08 ng*h/mL

Metabolite characterisation studies

Metabolites identified:

not measured