Changes in the pharmacokinetics of digoxin in polyuria in streptozotocin-induced diabetic mice and lithium carbonate-treated mice

Abstract

1. In humans, digoxin is mainly eliminated through the kidneys unchanged, and renal clearance represents approximately 70% of the total clearance. In this study, we used the mouse models to examine digoxin pharmacokinetics in polyuria induced by diabetes mellitus and lithium carbonate (Li₂CO₃) administration, including mechanistic evaluation of the contribution of glomerular filtration, tubular secretion, and tubular reabsorption.

2. After digoxin administration to streptozotocin (STZ)-induced diabetic mice, digoxin CL/F increased to approximately 2.2 times that in normal mice. After treatment with Li₂CO₃ (0.2%) for 10 days, the CL/F increased approximately 1.1 times for normal mice and 1.6 times for STZ mice.

3. Creatinine clearance (CLcr) and the renal mRNA expression levels of mdr1a did not differ significantly between the normal, STZ, and Li₂CO₃-treated mice.

4. The urine volume of STZ mice was approximately 26 mL/day, 22 times that of normal mice. The urine volume of Li₂CO₃-treated mice increased approximately 7.3 times for normal mice and 2.3 times for STZ mice.

5. These results suggest that the therapeutic effect of digoxin may be significantly reduced in the presence of polyuria either induced by diabetes mellitus or manifested as an adverse effect of Li₂CO₃ in diabetic patients, along with increased urine volume.

Keywords::

• Digoxin
• streptozocin-induced diabetic mice
• lithium carbonate
• renal clearance
• mdr1a
• aquaporin