Lanthanum chloride, anhydrous

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
See toxicokinetics, metabolism and distribution.

Additional information

Toxicokinetic data via the intravenous route are available for the water-soluble compound lanthanum trichloride. Additionally, there are oral pharmacokinetic studies published for the drug Fosrenol^® (Shire Pharmaceuticals), which contains lanthanum carbonate hydrate. Even though lanthanum carbonate is practically insoluble in water, it dissociates in the acid environment of the upper gastrointestinal tract and free lanthanum ions occur (Curran and Robinson, 2009). Based on the dissociation of lanthanum carbonate at resting stomach pH and the water solubility of lanthanum trichloride, soluble lanthanum ions result from both compounds. Thus, read across was conducted based on the structurally related compound lanthanum carbonate to supplement the toxicokinetic data of lanthanum trichloride.

 

Absorption

Soluble lanthanum ions bind dietary phosphate in the lumen of the gut and form highly insoluble lanthanum phosphate complexes. These complexes can not easily pass through the wall of the gastrointestinal tract and are excreted in the faeces. Therefore, the absorption of lanthanum from the gastrointestinal tract is expected to be very low (< 0.002%). After oral administration of lanthanum carbonate, poor absorption of lanthanum was experimentally confirmed in animals (Damment and Pennick, 2007) and in humans (Pennick et al., 2006).

In healthy humans intravenously administered lanthanum trichloride (120 µg elemental lanthanum over a 4-hour period) was well tolerated (Pennick et al., 2006). The mean plasma concentration of lanthanum increased to a maximum of 5.1 ± 0.9 ng/mL at 3.3 ± 0.8 hours after start of the infusion. Plasma lanthanum concentrations subsequently declined triphasically, with a mean terminal elimination half-life of 37 ± 22 hours. Lanthanum plasma exposure (mean AUC) after intravenous dosing was 38.9 ± 10.5 ng*h/mL. Following intravenous injection of 0.3 mg/kg lanthanum trichloride in rats, plasma lanthanum levels decreased rapidly from a peak of 3231 ± 233 ng/mL measured at 5 min, to approx. 14% of C_max by 2 h postdose. Thereafter, plasma concentrations declined at a slower rate and returned to 3.08 ± 2.91 ng/mL by 48 hours (Damment and Pennick, 2007).

Absorption of different lanthanoid chlorides from the skin is known to be negligible (Inaba and Yasumoto, 1979). However, when the skin was injured, lanthanoid chlorides seemed to be absorbed into the body to some extent (Inaba and Yasumoto, 1978; Takada, 1978).

 

Metabolism

Lanthanum is not metabolised and is neither a substrate nor an inhibitor of CYP450 (Pennick et al., 2003a).

 

Distribution/Excretion

After oral administration of lanthanum carbonate, intestinal epithelial cells appear to concentrate lanthanum and through normal exfoliation eject it back into the intestinal lumen for excretion (Floren et al., 2001; Fehri et al., 2005). The small fraction of absorbed lanthanum is extensively (> 99.7%) bound to plasma proteins (Damment and Pennick, 2007). In animal studies, absorbed lanthanum was widely distributed to systemic tissues, predominantly bone, liver and mesenteric lymph nodes (Slatopolsky et al., 2005; Lacour et al., 2005; Behets et al., 2004; Damment and Shen, 2005).

Following oral administration of lanthanum carbonate, the great majority of the dose is excreted unabsorbed in the faeces: 99% and 93% of the dose was recovered in the faeces of rats (Damment and Pennick, 2007) and dogs (Shire Pharmaceuticals, 2004), respectively. The small absorbed fraction is excreted predominantly via the liver into bile (Pennick et al., 2006; Damment and Pennick, 2007). Biliary elimination (80%) and direct transport across the gut wall into the lumen (13%) represent the main routes of elimination.

Following intravenous infusion of lanthanum trichloride in humans (Pennick et al., 2006), the total clearance of lanthanum (55 ± 15 mL/min) was low relative to average hepatic blood flow (1470 mL/min). Lanthanum was widely distributed with an apparent volume of distribution of 164 ± 84 L. Intravenous administration confirmed low renal clearance (0.95 ± 0.60 mL/min), just 1.7% of total plasma clearance. The systemic clearance of lanthanum in rats after a single intravenous 0.3 mg/kg dose of lanthanum trichloride was relatively low: 0.66 mL/(min*kg). It can be suggested that lanthanum was distributed into tissues, from where it was eliminated at a slower rate.

In human studies, fecal lanthanum excretion was not quantifiable after intravenous administration owing to the natural high background levels of lanthanum in faeces (Pennick et al., 2006). After a single intravenous 0.3 mg/kg dose of lanthanum trichloride in rats, recovery of lanthanum over 42 days was 76.4 ± 5.7% of the administered dose, predominantly in the faeces (Damment and Pennick, 2007). In contrast, only 1.94 ± 0.24% of the dose was excreted in urine over the 42-day collection period. The data imply that the kidneys are not significantly involved in the clearance of absorbed lanthanum.

The relatively low total recovery of lanthanum following intravenous administration (76.4% of the dose) is attributed in part to the protracted kinetics of lanthanum in tissues such as bone, and in part to a significant underestimation of faecal lanthanum excretion.

 

References:

Curran, M.P. and Robinson, D.M (2009). Lanthanum carbonate: a review of its use in lowering serum phosphate in patients with end-stage renal disease. Drugs 69(16): 2329-2349.

Inaba, J. and Yasumoto, M.S. (1979). A kinetic study of radionuclide absorption through damaged and undamaged skin of the guinea pig. Health Phy 37:592-595.

Takada, K. (1978). Comparison of the metabolic behaviour of 144Ce injected intravenously with that absorbed from the wound site in rats. Health Phy 35: 537-543

Marciniak, M. et al. (1988). The effect of toxic doses of lanthanum and cerium on the placental barrier and blood/organ barrier in mice after intravenous injection of these elements. Acta Physiol Pol 39: 294-299.

Pennick, M. et al. (2003). The pharmacokinetics and tissue distribution of lanthanum carbonate (Fosrenol), a novel non-aluminium, non-calcium phosphate binder [poster]. 36^thAnnual Meeting of the American Society of Nephrology (ASN), Nov 12-17;(CA).

Slatopolsky, E. et al. (2005). Progressive accumulation of lanthanum in the liver of normal and uremic rats. Kidney Int 68: 2809-2813.

Floren, C. et al. (2001). Analytical microscopy observations of rat enterocytes after oral administration of soluble salts of lanthanides, actinides and elements of group III-A of the periodic chart. Cell Mol Biol (Noisy-le-grand) 47: 419-425.

Fehri, E. et al. (2005). Lanthanides and microanalysis: effects of oral administration of two lanthanides: ultrastructural and microanalytical study. Arch Inst Pasteur 82: 59-67.

Lacour, B. et al. (2005). Chronic renal failure is associated with increased tissue deposition of lanthanum after 28-day oral administration. Kidney Int 67: 1062-1069.

Bush, V.J. et al. (1995). Essential and toxic element concentrations in fresh and formalin-fixed human autopsy tissues. Clin Chem 41: 284-294.

Bervoets, A.R. et al. (2007). Steady state liver lanthanum (LA) kinetics in chronical renal failure (CRF) rats are consistent with a transcellular lysosomal biliary excretion pathway. J Am Soc Nephrol 18 (abstracts issue): 304A-305A.

Behets, G.J. et al. (2004). Lanthanum carbonate: a new phosphate binder. Curr Opin Nephrol Hypertens 13: 403-409.

Damment, S.J.P. and Shen, V. (2005). Assessment of effects of lanthanum carbonate with and without phosphate supplementation on bone mineralization in uremic rats. Clin Nephrol 63: 127-137.

Shire Pharmaceuticals, (2004). Bioavailability and absorption of lanthanum carbonate in dialysis patients. Data on file.

Discussion on bioaccumulation potential result:

See toxicokinetics, metabolism and distribution.