title: Changes in the pharmacokinetics of digoxin in polyuria in streptozotocin-induced diabetic mice and lithium carbonate-treated mice.
abstract: 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 (Li(2)CO(3)) 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 Li(2)CO(3) (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 Li(2)CO(3)-treated mice. The urine volume of STZ mice was approximately 26 mL/day, 22 times that of normal mice. The urine volume of Li(2)CO(3)-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 Li(2)CO(3) in diabetic patients, along with increased urine volume.
authors.affiliation: Hoshi University, Department of Clinical Pharmacokinetics, Tokyo, Japan.
authors.forename: Nobutomo
authors.initials: N
authors.lastname: Ikarashi
authors.forename: Mai
authors.initials: M
authors.lastname: Kagami
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Ishii
authors.forename: Takahiro
authors.initials: T
authors.lastname: Toda
authors.forename: Wataru
authors.initials: W
authors.lastname: Ochiai
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Sugiyama
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D000928:Antidepressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D051399:Aquaporin 2 / Q000378:metabolism / Q000652:urine; D051400:Aquaporin 3 / Q000378:metabolism / Q000652:urine; D003404:Creatinine / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004077:Digoxin / Q000493:pharmacokinetics*; D004347:Drug Interactions; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D016651:Lithium Carbonate / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008954:Models, Biological; D011141:Polyuria / Q000139:chemically induced / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013311:Streptozocin
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; D000928:Antidepressive Agents; C496024:Aqp2 protein, mouse; C496028:Aqp3 protein, mouse; D051399:Aquaporin 2; D012333:RNA, Messenger; D051400:Aquaporin 3; D016651:Lithium Carbonate; D013311:Streptozocin; D004077:Digoxin; C095122:multidrug resistance protein 3; D003404:Creatinine