• Metabolism: Rapidly and extensively metabolized. The metabolic pathway of spironolactone is complex and can be divided into two main routes: those in which the sulfur moiety is retained and those in which the sulfur moiety is removed by dethioacetylation. Spironolactone is transformed to a reactive metabolite that can inactivate adrenal and testicular cytochrome P450 enzymes. It also has anti-androgenic activity. Route of Elimination: The metabolites are excreted primarily in the urine and secondarily in bile. Half Life: 10 minutes
• Uses/Sources: Used primarily to treat low-renin hypertension, hypokalemia, and Conn's syndrome.
• Symptoms: Acute overdosage of spironolactone may be manifested by drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Spironolactone has been shown to be a tumorigen in chronic toxicity studies in rats.
• Route of Exposure: Fairly rapidly absorbed from the gastrointestinal tract. Food increases the bioavailability of unmetabolized spironolactone by almost 100%.

• Carcinogenicity: 3, not classifiable as to its carcinogenicity to humans. (L135)
• Toxicity: The oral LD₅₀ of spironolactone is greater than 1,000 mg/kg in mice, rats, and rabbits.

Spironolactone is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents which act more proximally in the renal tubule. Aldosterone interacts with a cytoplasmic mineralocorticoid receptor to enhance the expression of the Na+, K+-ATPase and the Na+ channel involved in a Na+ K+ transport in the distal tubule . Spironolactone bind to this mineralcorticoid receptor, blocking the actions of aldosterone on gene expression. Aldosterone is a hormone; its primary function is to retain sodium and excrete potassium in the kidneys.