title: Lack of effect of bilateral nephrectomy on the pharmacokinetics of 14C-indapamide (REV 2555) and its metabolites in the dog.
abstract: Renal impairment can affect the disposition of metabolites, as well as unchanged drug, especially when there is significant renal clearance of metabolites. The pharmacokinetics of indapamide, a highly metabolized drug, and total indapamide equivalents (as an indicator of metabolites plus unchanged drug) were determined in the anephric dog. An intravenous dose of 14C-indapamide was administered to dogs first after a sham-operation, and then following bilateral nephrectomy. The disposition of total indapamide equivalents, calculated from total radioactivity, was not substantially different after nephrectomy as compared to after sham-operation, with an increase after nephrectomy in the area under the blood level curve (+26.2%), and decreases in the elimination rate constant (-6.9%), volume of distribution (-12.7%) and total blood clearance (-21.9%). The only statistically significant change was the decrease in the volume of distribution. The elimination kinetics of unchanged drug were also qualitatively similar in both cases. After nephrectomy, a decrease was seen in the elimination rate constant (-10.9%) and the volume of distribution (-16.3%) while slight increases in the total blood clearance (+1.9%) and the area under the blood level curve (+4.8%) were noted. These findings could have important implications for advantageous use of indapamide in treatment of hypertensive patients with renal failure since these data suggest that metabolites as well as unchanged drug could still be effectively eliminated by an alternate, non-renal route, thus minimizing accumulation of these compounds.
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D002250:Carbon Radioisotopes; D004232:Diuretics / Q000378:metabolism*; D004285:Dogs; D007190:Indapamide / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D008297:Male; D009392:Nephrectomy
chemical_list: D002250:Carbon Radioisotopes; D004232:Diuretics; D007190:Indapamide