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

• Published in: Xenobiotica 2011-06, Vol.41 (6), p.486-493
• Main Authors: Ikarashi, Nobutomo, Kagami, Mai, Kobayashi, Yasushi, Ishii, Makoto, Toda, Takahiro, Ochiai, Wataru, Sugiyama, Kiyoshi
• Format: Article
• Language: English
• Subjects: Animals; Anti-Arrhythmia Agents - pharmacokinetics; Antidepressive Agents - adverse effects; Antidepressive Agents - pharmacology; aquaporin; Aquaporin 2 - metabolism; Aquaporin 2 - urine; Aquaporin 3 - metabolism; Aquaporin 3 - urine; ATP Binding Cassette Transporter, Sub-Family B - genetics; ATP Binding Cassette Transporter, Sub-Family B - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Creatinine - metabolism; Diabetes Mellitus, Experimental - metabolism; Digoxin; Digoxin - pharmacokinetics; Drug Interactions; Kidney - drug effects; Kidney - metabolism; lithium carbonate; Lithium Carbonate - adverse effects; Lithium Carbonate - pharmacology; Male; mdr1a; Mice; Mice, Inbred ICR; Models, Biological; Polyuria - chemically induced; Polyuria - metabolism; renal clearance; RNA, Messenger - metabolism; Streptozocin; streptozocin-induced diabetic mice
• ISSN: 0049-8254; 1366-5928
• DOI: 10.3109/00498254.2011.551848

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