SPECIES-DIFFERENCES IN METABOLISM AND DISPOSITION OF SPIRONOLACTONE

  • 1 January 1976
    • journal article
    • research article
    • Vol. 4  (6) , 547-555
Abstract
The absorption, excretion and metabolism of 22-14C spironolactone was compared in Charles River rats, beagle dogs and rhesus monkeys. The drug was administered at the fixed dose of 5 mg/kg oral and i.v. From the oral/i.v. ratios of the areas under the plasma radioactivity-time curves, the gastrointestinal absorption of the drug was estimated to be 82% in the rat, 62% in the dog and 103% in the monkey. The absolute bioavailability of a pharmacologically active metabolite, canrenone, was 57% in the dog and 48% in the monkey. Spironolactone was extensively metabolized in all 3 species and differences existed in the composition of the metabolites in their plasma, urine and feces. The amount of radioactivity that was excreted in the urine and feces of all 3 species was similar after either oral or i.v. administration of the drug. The cumulative average excretion of radioactivity in the urine as percentage of the oral dose in 6 days was 4.69% in 5 rats, 18.5% in 3 dogs, and 46.0% in 3 monkeys. In the feces, the corresponding excretion values were 74.2, 69.3 and 40.1%, respectively. Canrenone excretion in the urine constituted 0.65% of the oral dose in the rat, 0.82% in the dog and 5.86% in the monkey; the excretion of total fluorogenic metabolites constituted 1.1, 1.9 and 12.1%, respectively. Comparison of animal data with those published for humans indicated that the disposition and metabolism of spironolactone in the rhesus monkey, rather than those in the rat or the dog, was closest to that in man.