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Lithium pharmacokinetics: single-dose experiments and analysis using a physiological model

B E Ehrlich, C Clausen, J M Diamond

    Journal of Pharmacokinetics and Biopharmaceutics
    |October 1, 1980
    PubMed
    Summary
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    This study tracked lithium distribution in healthy humans, revealing that intracellular lithium levels are below equilibrium, suggesting shared transport mechanisms between red blood cells and muscle. Circadian rhythms also influence lithium excretion.

    Area of Science:

    • Pharmacokinetics and Biopharmaceutics
    • Cellular Physiology
    • Human Physiology

    Background:

    • Lithium (Li+) is a mood-stabilizing drug with a complex distribution in the body.
    • Understanding lithium kinetics is crucial for optimizing therapeutic efficacy and minimizing toxicity.
    • Previous studies have focused on plasma concentrations, with less known about intracellular distribution and transport mechanisms.

    Purpose of the Study:

    • To investigate the kinetics of lithium distribution in plasma, erythrocytes (RBC), and urine after a single dose in healthy subjects.
    • To develop a physiologically realistic model to determine rate constants for lithium transport between body compartments.
    • To assess whether lithium transport mechanisms in RBCs are shared with other tissues, such as muscle, and to explore diurnal variations in lithium excretion.

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    Main Methods:

    • Simultaneous measurement of Li+ concentrations in plasma, RBCs, and urine following a single Li+ dose.
    • Fitting experimental data to a physiologically realistic kinetic model to extract rate constants.
    • Calculation of steady-state cell-to-plasma Li+ ratios for RBCs and inaccessible cells (muscle).
    • Comparison of model-derived rate constants with independent measurements of cellular transport.

    Main Results:

    • The study elucidated Li+ distribution kinetics in healthy humans, providing insights into its movement across different body compartments.
    • Calculated steady-state Li+ ratios for RBCs and muscle cells were significantly below electrochemical equilibrium.
    • Evidence suggests a shared Li+ countertransport efflux mechanism between RBCs and muscle cells.
    • A circadian rhythm in Li+ excretion was observed, mirroring daily Na+ and K+ excretion patterns.

    Conclusions:

    • Intracellular Li+ concentrations in both RBCs and muscle cells are maintained below electrochemical equilibrium, indicating active transport or regulatory mechanisms.
    • The findings support the hypothesis that the Li+ efflux mechanism in RBCs is also present in muscle tissue.
    • Lithium excretion exhibits a circadian rhythm, which may have implications for dosing strategies and monitoring.