(Inspra) and spironolactone (Aldactone) are both aldosterone antagonists that
can be used for the treatment of hypertension (HTN) and heart failure (HF) due
to left ventricular systolic dysfunction.1,2 In addition to these indications,
spironolactone is also used in the management of primary hyperaldosteronism,
edema from cirrhosis, and prophylaxis against hypokalemia.2
Additionally, spironolactone is available generically and is known to
have fewer drug interactions than compared to eplerenone.
reason eplerenone is subject to additional drug interactions versus
spironolactone have to do with the differences in their pharmacokinetic
profiles. When spironolactone is administered by mouth, over 65% of
spironolactone is absorbed and then undergoes first-pass metabolism in the
liver via non-cytochrome P450 (CYP) enzymes to its main active
metabolite, canrenone.2-4 Canrenone then acts as a competitive inhibitor
of aldosterone binding to the mineralocorticoid receptor.3,4 Similarly,
over 65% of eplerenone is absorbed, where it will also undergo metabolism in
the liver.1 However, eplerenone is primarily dependent on CYP3A4 for its
metabolism and elimination from the body and thus is prone to interactions with
other substrates or inhibitors of CYP3A4.
is well known that the CYP450 enzyme system is involved in the drug metabolism
of many medications used in clinical practice and have been implicated in
causing clinically relevant drug-drug interactions.5,6 There are a
number of CYP enzymes involved in mediating drug interactions, with CYP3A4 not
only being the most prevalent CYP enzyme in the liver, but is also used by more
than 50% of medications on the market for their metabolism and/or elimination
from the body.5-7 In addition, a large number of medications are known to
also inhibit the activity of CYP3A4.6,7 As such, medications that are
competitive or noncompetitive inhibitors of CYP3A4 can interact with the
metabolism of eplerenone. For example, ketoconazole at 200 mg twice daily
caused a 5.4-fold increase in the area under the curve (AUC) in eplerenone.1
Other known inhibitors of CYP3A4 such as erythromycin 500 mg twice daily,
verapamil 240 mg once daily, saquinavir 1200 mg three times a day and fluconazole
200 mg once daily are known to cause 2-2.9-fold increases in the AUC of
eplerenone.1 Without dosage reductions of eplerenone, drug interactions
such as these are likely to put the patient at greater risk of clinically
to the above drug interactions, the current Food and Drug Administration (FDA)
approved product package insert for eplerenone, recommends starting eplerenone
at lowers doses (25 mg daily) if the patient is already taking a
moderate-strong inhibitor of CYP3A4.1 This risk for hyperkalemia would be
further increased if a drug interaction with eplerenone were to occur in a
patient started on an angiotensin converting enzyme (ACE) inhibitor,
angiotensin receptor blocker (ARB), and/or with acute renal impairment or
failure, since these medications and changes in renal function can also put the
patient at increased risk for electrolyte abnormalities.
- Eplerenone (Inspra) product package insert. Pfizer Inc., Ney York, NY. April 2008.
E. Drugs affecting renal and cardiovascular function. In: Goodman
& Gilman's The Pharmacological Basis of Therapeutics. 11ed.
Brunton LL, Lazo JS, Parker KL eds. McGraw-Hill. New York, NY.
- Karim A. Spironolactone: disposition, metabolism, pharmacodynamics and bioavailability. Drug Metab Rev 1978;8:151-88.
JH, O'Donnell JP, Flowers L et al. Metabolism of spironolactone by
adrenocortical and hepatic microsomes: relationship to cytochrome P-450
destruction. J Pharmacol Exp Ther 1986;236:675-80.
S, Ci Carlo FJ. Human cytochrome P450 enzymes: a status report
summarizing their reactions, substrates, inducers, and inhibitors.
Drug Metab Rev 1997;29:413-580.
States Food and Drug Administration. Guidance for Industry. Drug
Interaction Studies - Study Design, Data Analysis, and Implications for
Dosing and Labeling. September 2006. Clinical Pharmacology. Accessed
last on 5/19/2009.
Y, Hisaka A, Suzuki H. General framework for the quantitative
prediction of CYP3A4-mediated oral drug interactions based on the AUC
increase by coadministration of standard drugs. Clin Pharmacokinet
B, Remme W, Zannad F et al. Eplerenone, a selective aldosterone
inhibitor, in patients with left ventricular dysfunction after
myocardial infarction. N Engl J Med 2003;348:1309-21.