Lithium therapy is always taken orally, usually as lithium carbonate as this causes least irritation to the stomach, to a total dose of up to 30 mmol (<2 g) per day. Treatment is monitored by blood concentration 12 h after administration. The therapeutic index for lithium, which represents the concentration window from efficacy to toxicity, is very narrow, occurring between 0.4 and 0.8 mM. Interestingly, lithium treatment alters magnesium balance, and concentrations of magnesium ions are altered in both the blood and the urine following lithium treatment. This is consistent with displacement of magnesium by lithium from cellular binding sites.
In general, lithium distributes uniformly among the body tissues, and most cells of the body experience an external lithium concentration of less than 2 mM, even at the highest clinical doses. However, local accumulation occurs in some tissues, but not those of the brain. In particular, lithium accumulates to a moderate degree in endocrine glands and to a high concentration at the tip of the papilla in the kidney. At a blood concentration of 1 mM, the renal papillary can reach 60-65 mM.
Lithium is not soluble in lipids and hence will not cross the plasma membrane. There are a number of routes for lithium entry into the cell - the most prevalent being lithium-sodium counter-transport,13 anion exchange14 and through other unrelated transport molecules. It is also not bound to proteins in plasma or tissue, unlike other BD treatments.
In addition to its therapeutic uses, embryologists have long known lithium to be a teratogen - a drug that affects patterning and proportion of cell types in the developing embryo. For example, in sea urchins, lithium causes vegetaliza-tion of the animal blastomeres,15 and in vertebrates such as Xenopus16 and zebrafish17 it causes expansion of the dorsal mesoderm and duplication of the dorsal axis. These effects are not restricted to animals, as lithium treatment of Dictyostelium, a non-metazoan eukaryote, leads to mis-specification of spore and basal disc cell fate.18 It was therefore assumed that lithium treatment will be teratogenic in humans, as seen for the other mood stabilizers valproic acid (VPA) and carbamazepine (CBZ).19 However, despite the assumed clinical risk, there are surprisingly few reports of teratogenic effects of lithium on human development, although some reports have suggested an increased risk of congenital heart defects.19 The difference in these teratogenic rates may reflect dosage, as embryological experiments carried out in the laboratory generally use higher than therapeutic lithium concentrations.
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