Analytical strategies for the measurement of lithium in biological samples

Therapeutic lithium levels in the treatment of manic depressive psychosis must be maintained in the range of 0.5-1.5 mM in the blood, which also contains 140 mM sodium. This paper reviews spectrophotometric, fluorometric, and ion-selective electrode (ISE) reagents and methods for achieving high lithium selectivity over sodium and their use in blood lithium measurement. These include aromatic organic reagents, crown ethers and amide ionophores. Crown ethers and cryptands provide the best lithium selectivity. A chromophoric small-cavity cryptand phenol exhibits greater than 4000:1 selectivity due to rigid configuration of a well preorganized binding site for lithium complexation. It is water soluble, making it easy to apply for blood analysis. Crown ethers with bulky groups inhibit formation of the 2:1 crown:sodium complex, while allowing formation of the 1:1 lithium complex. A PTM 14-crown-4 having a bulky pinane and subunits at the ethano bridge exhibits at least 10,000:1 selectivity for lithium in a flow-through optical sensor probe. Bulky crown ethers used in PVC membrane ion-selective electrodes exhibit lithium selectivities of 1-2000:1. Methods of evaluating selectivities are discussed, along with the correlation of solvent extraction of crown ether complexes and solvent membrane ISE selectivities.