Lithium is one of the mainstays for the treatment of bipolar disorder despite its
side effects on the endocrine, neurological, and renal systems. Experimentally, lithium
has been used as a measure to determine proximal tubule reabsorption based on the
assumption that lithium and sodium transport go in parallel in the proximal tubule.
However, the exact mechanism by which lithium is reabsorbed remains elusive. The majority
of proximal tubule sodium reabsorption is directly or indirectly mediated by the sodium-hydrogen
exchanger 3 (NHE3). In addition, sodium-phosphate cotransporters have been implicated
in renal lithium reabsorption. In order to better understand the role of sodium-phosphate
cotransporters involved in lithium (re)absorption, we studied lithium pharmacokinetics
in: i) tubule-specific NHE3 knockout mice (NHE3 loxloxPax8Cre ), and ii) mice challenged
with low or high phosphate diets. Intravenous or oral administration of lithium did
not result in differences in lithium bioavailability, half-life, maximum plasma concentrations,
area under the curve, lithium clearance, or urinary lithium/creatinine ratios between
control and NHE3 loxloxPax8Cre mice. After one week of dietary phosphate challenges,
lithium bioavailability was ~30% lower on low versus high dietary phosphate, possibly
the consequence of a smaller area under the curve after oral administration. This
was associated with lower lithium clearance after oral administration and lower urinary
lithium/creatinine ratios on low versus high dietary phosphate. Collectively, renal
NHE3 does not play a role in lithium pharmacokinetics; however, dietary phosphate
could have an indirect effect on lithium bioavailability and lithium disposition.