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

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  • Author(s): Pacholko AG;Pacholko AG; Bekar LK; Bekar LK
  • Source:
    Journal of psychiatric research [J Psychiatr Res] 2023 Aug; Vol. 164, pp. 192-201. Date of Electronic Publication: 2023 Jun 17.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Pergamon Press Country of Publication: England NLM ID: 0376331 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-1379 (Electronic) Linking ISSN: 00223956 NLM ISO Abbreviation: J Psychiatr Res Subsets: MEDLINE
    • Publication Information:
      Original Publication: Oxford : Pergamon Press
    • Subject Terms:
      Lithium Carbonate*/adverse effects ; Bipolar Disorder*/drug therapy; Male ; Female ; Mice ; Animals ; Mania/chemically induced ; Mania/drug therapy ; Lithium/therapeutic use ; Amphetamine/therapeutic use ; Disease Models, Animal ; Antimanic Agents/pharmacology
    • Abstract:
      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 unique uptake characteristics 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. 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. LiCO induced a partial block of AIH at doses of 15 mg/kg in males and 20 mg/kg 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 organic anion transport inhibitors, or inhibition of orotate uptake into the pentose pathway, completely blocked the effects of LiOr on AIH while sparing LiCO effects, confirming differences in transport and compartmentalization between the two compounds. Next, the relative toxicities of LiOr and LiCO were contrasted after 14 consecutive daily administrations. LiCO, but not LiOr, elicited polydipsia in both sexes, elevated serum creatinine levels in males, and increased serum TSH expression in females. LiOr demonstrates superior efficacy, potency, and tolerability to LiCO in both male and female mice because of select transport-mediated uptake and pentose pathway incorporation.
      Competing Interests: Declaration of competing interest Dr. Bekar and Mr. Pacholko report no biomedical financial interests or potential conflicts of interest.
      (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
    • Contributed Indexing:
      Keywords: Amphetamine-induced hyperlocomotion; Bipolar disorder; Lithium; Mania; Orotate
    • Accession Number:
      2BMD2GNA4V (Lithium Carbonate)
      L2N7Z24B30 (lithium orotate)
      9FN79X2M3F (Lithium)
      CK833KGX7E (Amphetamine)
      0 (Antimanic Agents)
    • Publication Date:
      Date Created: 20230625 Date Completed: 20230719 Latest Revision: 20230720
    • Publication Date:
      20240829
    • Accession Number:
      10.1016/j.jpsychires.2023.06.012
    • Accession Number:
      37356352