Different pharmacokinetics of lithium orotate inform why it is more potent, effective, and less toxic than lithium carbonate in a mouse model of mania

Objective Lithium carbonate (LiCO) is a mainstay therapeutic for the prevention of mood-episode recurrences in bipolar disorder (BD). Unfortunately, its narrow therapeutic index is associated with complications that may lead to treatment non-compliance. Intriguingly, lithium orotate (LiOr) is suggested to possess uptake properties that would allow for reduced dosing and mitigation of toxicity concerns. We hypothesized that due to differences in pharmacokinetics, LiOr is more potent with reduced adverse effects. Methods Dose responses were established for LiOr and LiCO in male and female mice using an amphetamine-induced hyperlocomotion (AIH) model; AIH captures manic elements of BD and is sensitive to a dose-dependent lithium blockade. Next, the relative toxicities of LiOr and LiCO were contrasted after 14 consecutive daily administrations. Results LiCO maintained a partial block of AIH at doses of 15 mg/kg or greater in males and 20 mg/kg or greater in females. In contrast, LiOr elicited a near complete blockade at concentrations of just 1.5 mg/kg in both sexes, indicating improved efficacy and potency. Prior application of an organic-anion transporting polypeptide 1A2 (OATP1A2) inhibitor completely blocked the effects of LiOr on AIH while sparing LiCO, suggesting differences in transport between the two compounds. LiCO, but not LiOr, elicited polydipsia in both sexes, elevated serum creatinine levels in males, and increased serum TSH expression in females. Conclusions LiOr demonstrates superior efficacy, potency, and tolerability to LiCO in both male and female mice as a result of select transport-mediated uptake.