Lithium chloride and dilithium carbamyl phosphate: Lithium distribution and toxicity in mice

Dilithium carbamyl phosphate, an antisickling agent, dissociates into lithium cations and carbamyl phosphate dianions in solution. In order to determine which ion is primarily responsible for the toxicity observed at very high doses of dilithium carbamyl phosphate, two groups of 15 mice each were given similar amounts of lithium in twice-daily ip injections for 21, 23, or 30 days. Six of the fifteen mice survived in group A (lithium chloride, 12.9 mEq of Li⁺/kg/day), and 8 of 15 mice survived in group B (dilithium carbamyl phosphate, 13.8 mEq of Li⁺/kg/day). Blood lithium concentrations measured 4–6 hr after an injection averaged 1.7 (±0.7 SD) mEq/liter for each group. Lithium concentrations were measured in 39 samples of tissue or tissue contents from mice in each group. In the surviving animals, lithium ranged from an average of 0.8 – 1.1 mEq/kg in liver to 5–15 mEq/kg in the contents of the lower intestinal tract. Lithium concentrations greater than 15 mEq/kg were often found in the tissues of the nonsurvivors. Hemoglobin carbamylation was 1.0 (±0.3 SD) mol of valine hydantoin/mol of hemoglobin tetramer in mice given dilithium carbamyl phosphate for 21–30 days. This study demonstrates that the toxic effects associated with administration of dilithium carbamyl phosphate appear to be due to the lithium cation rather than the carbamyl phosphate dianion. In all parameters measured, the toxic effects of lithium chloride paralleled those observed when an equivalent amount of lithium was administered as dilithium carbamyl phosphate.