Role of NHE3 and dietary phosphate in lithium pharmacokinetics

Abstract

Lithium (Li+) is one of the mainstays for the treatment of bipolar disorder despite its side effects on the endocrine, neurological, and renal systems. Experimentally, Li+ has been used to determine proximal tubule (PT) reabsorption based on the assumption that Li+ and Na+ transport go in parallel in the PT. However, the exact mechanism by which Li+ is reabsorbed remains elusive. The majority of PT Na+ reabsorption is directly or indirectly mediated by the Na+‐H+ exchanger 3 (NHE3). In addition, Na+‐phosphate cotransporters (Npt2a/c) have been implicated in renal Li+ reabsorption. We hypothesized that either NHE3 and/or Npt2a/c are mediating Li+ reabsorption. We studied Li+ pharmacokinetics in: i) tubule‐specific NHE3 knockout mice (NHE3loxloxPax8Cre), and ii) mice challenged with low or high phosphate diets. Intravenous (LiCl 5 mmol/kg, 2 μl/g BW) or oral administration (5 mmol/kg, 1% of BW via oral gavage) of LiCl did not result in differences in Li+ bioavailability (~80% in all groups), half‐life or urinary Li+/creatinine ratios between control and NHE3loxloxPax8Cre mice. After one week of dietary phosphate challenges, Li+ bioavailability was ~30% lower on low vs high dietary phosphate (64±4 vs 93±3%, P<0.05), possibly the consequence of a smaller area under the curve after oral administration (21±1 vs 25±1 mmol × L−1 × h, P<0.05). This was associated with lower urinary Li+/creatinine ratios on low vs high dietary phosphate (15±2 vs 47±7 mmol/mmol, P<0.05). Our data indicate that renal NHE3 does not play a role in Li+ pharmacokinetics; however, dietary phosphate has an indirect effect on Li+ bioavailability and Li+ disposition.Support or Funding InformationTR is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (1R01DK110621). JX was supported by an American Heart Association Predoctoral Fellowship (18PRE33990236) and LT by a Postdoctoral Fellowship (19POST34400026).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.