Evaluation of the potential genotoxicity of the phosphate binder lanthanum carbonate.
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.
Damment
S J P
SJ
Biosciences, Shire Pharmaceutical Development Ltd, Chineham, Basingstoke, UK and Covance Laboratories Ltd, Harrogate, North Yorkshire, UK. sdamment@uk.shire.com
Beevers
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Gatehouse
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D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007811:Lanthanum / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D009153:Mutagens / Q000378:metabolism / Q000494:pharmacology*; D010755:Organophosphates / Q000378:metabolism*; D010710:Phosphates / Q000378:metabolism*; D051381:Rats
D009153:Mutagens; D010755:Organophosphates; D010710:Phosphates; C028521:lanthanum chloride; C119467:lanthanum carbonate; D007811:Lanthanum; D007041:Hypoxanthine Phosphoribosyltransferase