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Toxicological information

Basic toxicokinetics

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

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:
Lanthanum chloride was administered by intravenous injection in rats and the plasma lanthanum concentration was determined (two independent experiments with different single doses).
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Lanthanum chloride
- Analytical purity: no data
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River UK Ltd. (Margate, UK) or Harlan UK Ltd. (Bicester, UK).
- Weight at study initiation: 140-192 g

Administration / exposure

Route of administration:
intravenous
Vehicle:
other: sodium chloride
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Lanthanum chloride was formulated in sterile 0.9% (w/v) sodium chloride.
Duration and frequency of treatment / exposure:
single dose
Experiment 1: 24 h exposure duration
Experiment 2: 72 h exposure duration
Doses / concentrations
Remarks:
Doses / Concentrations:
Experiment 1: 0.03 mg/kg lanthanum chloride (0.017 mg/kg elemental lanthanum)
Experiment 2: 0.3 mg/kg lanthanum chloride (0.17 mg/kg elemental lanthanum)
No. of animals per sex per dose:
Experiment 1: two or three animals per sex, per time point (total number: n = 18)
Experiment 2: total number: n = 21 (only males)
Control animals:
yes, concurrent vehicle
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution)
- Tissues and body fluids sampled: blood, plasma
- Time and frequency of sampling: Experiment 1: pre-dose, 15 min., 1, 2, 4, 8 and 24 h after administration; Experiment 2: pre-dose, 5, 10, 20 and 40 min., 1, 2, 4, 8, 12, 18, 24, 48, 72 h

PREPARATION
- 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.
- 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 (AUC 0–24), and from time 0 to the last sample collection time (AUC last) were calculated using linear trapezoidal summation from time 0 to the appropriate time point. Total clearance (CL) following intravenous administration was calculated as Dose IV/AUC IV, and volume of distribution (Vz) was calculated as CL/k, where k was the terminal rate constant calculated following log-linear regression analysis of the linear phase of the concentration–time profile.

Results and discussion

Preliminary studies:
no data

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Experiment 1: AUC 0-24: 45.07 ng*h/mL (no further information given)
Experiment 2: Following intravenous injection of 0.3 mg/kg lanthanum chloride (the maximum tolerated intravenous dose established in previous studies), plasma lanthanum levels decreased rapidly from a peak of 3231±233 ng/mL measured at 5 min, to approximately 14% of Cmax by 2 h postdose. Thereafter, plasma concentrations declined at a slower rate and returned to pre-dose concentrations (3.08 ± 2.91 ng/mL) by 48 h.
Details on distribution in tissues:
Experiment 2:
The systemic clearance of lanthanum was relatively low: 0.66 mL/(min. kg). Combined with a Vz (volume of distribution) of 1.30 L/kg that exceeded total body water (0.7 L/kg), it can be suggested that lanthanum was distributed into tissues, from where it was eliminated at a slower rate. The whole blood to plasma lanthanum ratio based on AUC last was calculated as 0.55, indicating that very little lanthanum entered or was bound to red blood cells.
Details on excretion:
no data
Toxicokinetic parameters
Test no.:
#2
Toxicokinetic parameters:
Cmax: 3231+/-233 mg/mL

Metabolite characterisation studies

Metabolites identified:
not measured

Applicant's summary and conclusion