Spironolactone Pharmacokinetics (ADME): Absorption, Metabolism, and Clinical Implications

Print or save as PDF

See the public record for Spironolactone

The numbers the label gives

The current Aldactone label reports a mean time to peak plasma concentration of 2.6 hours for spironolactone and 4.3 hours for canrenone, and mean half-lives of 1.4 hours for spironolactone, 16.5 hours for canrenone, 13.8 hours for TMS and 15 hours for HTMS [1]. Protein binding is greater than 90% [1]. The metabolites are excreted primarily in the urine and secondarily in bile [1].

Spironolactone itself has a short mean half-life of 1.4 hours, while its metabolites have mean half-lives of 13.8 to 16.5 hours, so metabolite exposure lasts considerably longer than exposure to the parent drug [1].

Absorption and the food effect

Food increased the bioavailability of spironolactone, measured as AUC, by approximately 95% [1]. That is close to a doubling of exposure from the same tablet.

The prescribing information allows Aldactone to be taken with or without food and says it should be taken consistently with respect to food [1].

Metabolism: two families of metabolites

Spironolactone is rapidly and extensively metabolized [1]. The label sorts the metabolites into two categories: those in which the sulfur of the parent molecule is removed, with canrenone as the example, and those in which the sulfur is retained, namely TMS and 6-beta-hydroxy-7-alpha-thiomethylspironolactone (HTMS) [1].

The label names no cytochrome P450 enzyme for this metabolism and its drug interaction section lists no CYP-based interactions [1].

Canrenone was long assumed to be the main metabolite. Once specific high-performance liquid chromatography assays replaced earlier methods, 7-alpha-thiomethylspirolactone (TMS) turned out to be the major metabolite in serum after a single oral dose, with unchanged spironolactone reaching maximum concentrations of the same order as canrenone [2]. A 15-day study in 12 healthy men concluded that TMS rather than canrenone is the major serum metabolite after single or repeated doses [3].

Potency differs by compound. In humans, TMS and 7-alpha-thiospirolactone reversed the effect of fludrocortisone on urinary electrolyte composition with about one third of spironolactone's potency [1]. The label also states that spironolactone binds the androgen receptor, which is the basis of its anti-androgenic effects [1], and one review suggests the endocrine effects such as gynecomastia are likely mediated by the sulfur-containing compounds [2].

Steady-state exposure

In the 15-day study of 12 healthy men taking spironolactone 100 mg once daily, day-15 peak serum concentrations were 80 ng/mL for spironolactone, 181 ng/mL for canrenone, 391 ng/mL for TMS and 125 ng/mL for HTMS [3]. The 24-hour AUC on day 15 was 231 ng·hr/mL for spironolactone, 2173 for canrenone, 2804 for TMS and 1727 for HTMS [3]. TMS, not canrenone, was the dominant circulating species, and its half-life of 13.8 hours is close to canrenone's 16.5 hours [1][3].

Acne and the label

Acne is not a labeled indication for spironolactone; the labeled uses are heart failure, add-on hypertension, edema and primary hyperaldosteronism [1].

The SAFA trial included 410 women aged 18 or older with facial acne for at least six months, randomized to spironolactone 50 mg/day to week 6 then 100 mg/day to week 24, or placebo [4]. Investigator's Global Assessment success at week 12 was 18.5% with spironolactone versus 5.6% with placebo (adjusted odds ratio 5.18, 95% CI 2.18 to 12.28), and the Acne-Specific Quality of Life symptom subscale favored spironolactone by 1.27 points at 12 weeks and 3.77 points at 24 weeks [4].

Potassium and renal monitoring

The label says to monitor serum potassium within one week of starting or titrating spironolactone and regularly thereafter, more often with other potassium-raising drugs or impaired renal function; if hyperkalemia occurs, the label says to decrease the dose or discontinue and treat the hyperkalemia [1]. The label says the risk is increased by impaired renal function, potassium supplements, potassium-containing salt substitutes, and drugs that increase potassium such as ACE inhibitors and angiotensin receptor blockers; it also names NSAIDs, heparin and low molecular weight heparin, and trimethoprim as drugs that can raise potassium [1]. The label also notes that spironolactone reduces the renal clearance of lithium, raising the risk of lithium toxicity [1].

In a retrospective study of 974 healthy young women taking spironolactone for acne, there were 13 abnormal potassium values among 1802 measurements (0.72%), matching a 0.76% baseline rate in 1165 comparison women, and 6 of the 13 repeats were normal; women with heart or kidney disease or on drugs affecting the renin-angiotensin system were excluded [5]. A systematic review of oral spironolactone for acne noted that pooled potassium data supported the conclusion that routine monitoring is not required in that population [6]. The Aldactone label still gives the monitoring instruction described above [1].

Special populations

The label states that the impact of age, sex, race/ethnicity and renal impairment on spironolactone pharmacokinetics has not been specifically studied [1]. In hepatic impairment with cirrhotic ascites, the terminal half-life of spironolactone has been reported to be increased, and the label warns that sudden fluid and electrolyte shifts can precipitate worsening hepatic encephalopathy and coma [1]. The label says patients with renal impairment are at increased risk of hyperkalemia and may have a greater risk of adverse reactions, and it advises close potassium monitoring [1]. On pregnancy, the label says to avoid spironolactone in pregnant women or advise of the potential risk to a male fetus, citing its anti-androgenic properties and rat data showing feminization of male fetuses; limited human case reports did not show an association with major malformations [1].

A note on eplerenone

The label lists concomitant use of eplerenone with spironolactone as a contraindication [1]. One review describes eplerenone as selective for aldosterone receptors alone, with lesser affinity for progesterone and androgen receptors, a shorter half-life than spironolactone, and no active metabolites [7].