Pharmacokinetics and pharmacodynamics of azosemide after intravenous and oral administration to rats: Absorption from various GI segments

Azosemide, 5, 10, 20, and 30 mg/kg, was administer ed both intravenously and orally to determine the pharmacokinetics and pharmacodynamics of azosemide in rats (n = 7-12). The absorption of azosemide from various segments of GI tract and the reasons for the appearance of multiple peaks in plasma concentrations of azosemide after oral administration were also investigated. After intravenous (iv) dose, the pharmacokinetic parameters of azosemide such as t(1/2) MRT, V-ss, CL, CLR, and CLNR, were found to be dose-dependent in the dose ranges studied. The percentages of the iv dose excreted in 8-hr urine as azosemide, M1 (a metabolite of azosemide), glucuronide of azosemide, and glucuronide of M1-expressed in terms of azosemide-were also dose-dependent in the dose ranges studied. The data above suggest saturable metabolism of azosemide in rats. The measurements taken after the iv administrations such as the 8 hr urine output, the total amount of sodium and chloride excreted in 8-hr urine per 100 g body weight, and diuretic, natriuretic, kaluretic, and chloruretic efficiencies were also shown to be dose-dependent. However, the total amount of potassium excreted in 8-hr urine per 100 g body weight was dose-independent. Similar dose-dependency was also observed following oral administration. Azosemide was absorbed from all regions of GI tract studied and approximately 93.5, 79.1, 86.1, and 71.5% of the doses (5, 10, 20, and 30 mg/kg, respectively) were absorbed between 1 and 24 hr after oral ac(ministration. The appearance of multiple peaks after oral administration is suspected to be due mainly to the gastric emptying pattern. The percentages of azosemide absorbed from the GI tract as unchanged azosemide for up to 24 hr after oral noses of 5, 10, 20, and 30 mg/kg were significantly different with noses (decreased with increasing doses), suggesting that the problem of azosemide precipitating in acinic gastric juices or dissolution may have at least partially influenced the absorption of azosemide after oral administration.