Evaluation of the potential genotoxicity of the phosphate binder lanthanum carbonate

Abstract

Lanthanum was evaluated for potential genotoxicity using a range of in vitro assays (as the carbonate) in the presence and absence of post-mitochondrial fraction (S9) and in vivo in three independent tests for mutagenicity and clastogenicity (as the carbonate and chloride). The drug was devoid of mutagenic activity in bacterial assays (maximum concentration 5000 microg/plate) using a range of test strains (Salmonella typhimurium TA1535, TA1537, TA1538, TA98, TA100 and TA102 and Escherichia coli WP2 uvrA and WP2 uvrA pkm101). No effects were seen in the hgprt gene mutation assay in Chinese hamster ovary cells in the presence of S9. In the absence of S9, sporadic increases in revertant numbers were not dose-related or reproducible in subsequent experiments and hence were concluded to be chance events. In an in vitro chromosome aberration assay using Chinese hamster ovary cells, chromosome damage in the presence and absence of S9 (concentration 200-5000 microg/ml) was attributed to overt cell toxicity. To confirm this, a comprehensive in vivo evaluation of the drug was performed. Negative results were obtained in two independent rodent micronucleus tests. In the first mice were given oral doses (of carbonate) up to 2000 mg/kg, in the second rats were given a single i.v. bolus injection (of chloride) up to 0.1 mg/kg. Negative results were also obtained in a rat liver unscheduled DNA synthesis assay after treatment for 28 days with i.v. bolus injections (of chloride) up to 0.1 mg/kg/day. In these in vivo studies lanthanum plasma concentrations were >3000 times higher than the steady-state peak plasma concentration observed in dialysis patients given therapeutic doses of lanthanum carbonate. It can be concluded that lanthanum is not genotoxic and that lanthanum carbonate is unlikely to present a latent hazard in therapeutic use.

Absolute Bioavailability and Disposition of Lanthanum in Healthy Human Subjects Administered Lanthanum Carbonate

“…In toxicology studies, it was well tolerated in both normal and uremic (5/6th nephrectomized) animals at doses up to 20 times those recommended for clinical treatment, with no aluminum-like toxicities or other effects of concern for clinical use. [11][12][13] The safety evaluation program included lifetime administration studies in mice and rats. After intravenous dosing, the primary target organ for toxicity was the liver, with significant effects occurring at plasma lanthanum concentrations 20 000 times higher than steady-state levels in dialysis patients.…”

Influence of Carnicor, Venofer, and Sevelamer on the levels of genotoxic damage in end‐stage renal disease patients

“…DOI 10.1002/em 2010). No genotoxicity data exist on this compound although another phosphate binder, called lanthanum, has shown to be nongenotoxic both in vitro and in vivo assays (Damment et al, 2005). Our results show that patients who took this drug do not have any increase in the levels of DNA damage observed either by the comet or by the micronucleus assays.…”

“…Brewster et al (2005) found that, although increased microbial colonization of catheters after iron administration exists, intravenous iron administration was not associated with acute microbial growth or clinical infection. No genotoxicity data exist on this compound although another phosphate binder, called lanthanum, has shown to be nongenotoxic both in vitro and in vivo assays (Damment et al, 2005). Sevelamer is a calcium-free, metal-free phosphate binder that offers control of hyperphosphatemia without increasing calcium levels, which would accelerate blood vessel calcification, decreasing serum levels of phosphorus and parathyroid hormone (PTH) in HD patients (Chertow et al, 2002;Pieper et al, 2006).…”

Cytocompatibility of a free machining titanium alloy containing lanthanum

“…Lanthanum is administered as a phosphate binder in chronic renal failure as lanthanum carbonate. In the course of the clinical trials many studies were performed which showed no toxicity, although lanthanum accumulated in different organs 22, 23. With respect to bone Bervoets et al showed an osteomalacia in lanthanum carbonate treated rats in combination with an accumulation of lanthanum in the bone 24.…”