Liver and Gastrointestinal First-pass Effects of Azosemide in Rats

Abstract

Abstract Since considerable first-pass effects of azosemide have been reported after oral administration of the drug to rats and man, first-pass effects of azosemide were evaluated after intravenous, intraportal and oral administration, and intraduodenal instillation of the drug, to rats. The total body clearances of azosemide after intravenous (5 mg kg−) and intraportal (5 and 10 mg kg−) administration of the drug to rats were considerably smaller than the cardiac output of rats suggesting that the lung or heart first-pass effect (or both) of azosemide after oral administration of the drug to rats was negligible. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) after intraportal administration (5 mg kg−) of the drug was significantly lower than that after intravenous administration (5 mg kg−) of the drug (1000 vs 1270 μg min mL−) suggesting that the liver first-pass effect of azosemide was approximately 20% in rats. The AUC from time 0 to 8 h (AUC0–8 h) after oral administration (5 mg kg−) of the drug was considerably smaller than that after intraportal administration (5 mg kg−) of the drug (271 vs 1580 μg min mL−) suggesting that there are considerable gastrointestinal first-pass effects of azosemide after oral administration of azosemide to rats. Although the AUC0–8 h after oral administration (5 mg kg−) of azosemide was approximately 15% lower than that after intraduodenal instillation (5 mg kg−) of the drug (271 vs 320 μg min mL−), the difference was not significant, suggesting that the gastric first-pass effect of azosemide was not considerable in rats. Azosemide was stable in human gastric juices and pH solutions ranging from 2 to 13. Almost complete absorption of azosemide from whole gastrointestinal tract was observed after oral administration of the drug to rats. The above data indicated that most of the orally administered azosemide disappeared (mainly due to metabolism) following intestinal first-pass in rats.