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EC number: 209-599-5 | CAS number: 587-26-8
- Life Cycle description
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Endpoint summary
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Description of key information
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Additional information
There are oral pharmacokinetic studies available for lanthanum carbonate. The drug Fosrenol® (Shire Pharmaceuticals) contains lanthanum carbonate hydrate which is orally administered as chewable tablet. The available Fosrenol® studies were used to describe the toxicokinetic properties of lanthanum carbonate. Fosrenol® is used as a phosphate binder for treatment of hyperphosphatemia in patients with chronic kidney disease who are undergoing dialysis (Damment and Pennick, 2008).
Absorption
Lanthanum carbonate is practically insoluble in water, but it dissociates in the acid environment of the stomach and free lanthanum ions are released (Curran and Robinson, 2009). Soluble lanthanum ions bind dietary phosphate in the lumen of the gut, forming 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 considered 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).
Pennick et al. (2006) showed that lanthanum was poorly absorbed after oral administration, when lanthanum carbonate was given as tablets (1000 mg elemental lanthanum) to healthy human volunteers. A mean Cmax of 0.32±0.13 ng/mL was reached at 4.5±0.8 hours after dosing. Thereafter, lanthanum plasma concentrations seemed to decline biphasically or triphasically, with a mean terminal elimination half-life of 35±12 hours. However, lanthanum plasma concentrations were generally below the limit of quantification after 48 hours postdose, and estimates of terminal elimination half-life should therefore be interpreted with caution. Systemic exposure to lanthanum was low, with a mean AUC of 3.9±2.5 ng*h/mL. Mean absolute bioavailability was extremely low at 0.00127±0.0008% in healthy subjects receiving oral lanthanum carbonate. The oral bioavailability in rats was estimated to be ≤ 0.0007% after oral administration of lanthanum carbonate (Damment and Pennick, 2007).
In healthy volunteers, plasma AUC and Cmax increased as a function of dose, but in a less than proportional manner after single oral doses of 250 to 1000 mg lanthanum, consistent with dissolution-limited absorption.
Based on the physico-chemical properties of the substance, e. g. poor water solubility and at the same time lack of lipophilicity, skin absorption is assumed to be negligible. In an acute dermal toxicity study, dose levels up to 2000 mg/kg bw Lanthanum carbonate were administered to albino rabbits (Ward, 1976). No signs of systemic or organ toxicity were recorded and no deaths occured indicating primarily a low dermal toxicity.
Metabolism
Lanthanum is not metabolised and is neither a substrate nor an inhibitor of CYP450 (Pennick et al., 2003).
Distribution
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).
In animal studies, absorbed lanthanum was widely distributed to systemic tissues, predominantly bone, liver and the gastrointestinal tract, including the mesenteric lymph nodes. In long-term animal studies, lanthanum concentrations in several tissues, including the gastrointestinal tract, bone and liver increased over time to levels several orders of magnitude above those in plasma. An apparent steady-state level of lanthanum was attained in some tissues, e.g. the liver whereas levels in the gastrointestinal tract increased with duration of treatment. In animal studies the liver is consistently reported to contain the highest tissue concentration of lanthanum (Slatopolsky et al., 2005; Lacour et al., 2005). However, the levels are very low compared with the natural hepatic levels of metals such as iron and copper (Bush et al., 1995). Irrespective of the duration of treatment, no animal experiments have shown liver concentrations exceeding 3 µg/g wet weight after oral administration of lanthanum carbonate (Bervoets et al., 2007). Bone is the only other tissue that consistently shows concentrations of lanthanum above 1 µg/g in animal distribution studies (Slatopolsky et al., 2005; Behets et al., 2004; Damment and Shen, 2005). No adverse effects were associated with the tissue deposition of lanthanum seen in long-term animal studies with high oral doses of lanthanum carbonate.
Excretion
After oral administration of lanthanum carbonate, the great majority of the dose is excreted unabsorbed in the faeces. Although this has not been demonstrated experimentally in humans, supporting evidence has been obtained from animal studies: 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. This implies that the kidneys are not significantly involved in the clearance of absorbed lanthanum from the human body. After a lanthanum administration of 1 g/day to healthy volunteers, only 0.00003% of the dose was excreted in the urine (Damment and Gill, 2003). In rats, orally administered lanthanum carbonate (306 mg/kg elemental lanthanum), 0.0035% of the dose were recovered in urine (Damment and Pennick, 2007). The presence of lanthanum in the liver (Das et al., 1988) is consistent with excretion of lanthanum by the liver.
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.
Pennick, M. et al. (2003). The pharmacokinetics and tissue distribution of lanthanum carbonate (Fosrenol), a novel non-aluminium, non-calcium phosphate binder [poster]. 36thAnnual 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 minceralization in uremic rats. Clin Nephrol 63: 127-137.
Shire Pharmaceuticals, (2004). Bioavailability and absorption of lanthanum carbonate in dialysis patients. Data on file.
Damment, S.J.P. and Gill, M. (2003). The pharmacokinetics and tissue distribution of lanthanum carbonate (Fosrenol®), a new non-aluminium, non-calcium phosphate binder (abstract). J Am Soc Nephrol 14: 204A.
Das, T. et al. (1988). Effects of lanthanum in cellular systems. Biological trace element research 18: 201-228.
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