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Why is Eplerenone (Inspra) More Drug Interactions than Spironolactone (Aldactone)?

Summary:

  • Eplerenone (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.
  • Spironolactone differs from eplerenone, not only by some additional indications, but spironolactone is available generically and is known to have fewer drug interactions compared to eplerenone.
  • 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, whereas spironolactone is not dependent on CYP enzymes for its metabolism and/or elimination.
  • As such, medications that are inhibitors of CYP3A4 can interact with the metabolism of eplerenone and thereby putting the patient at increased risk for hyperkalemia.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed: August 2015

Explanation

  • Eplerenone (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. 

    The 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. 

    It 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 relevant hyperkalemia.1,8 

    Due 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.

    References:

    1. Eplerenone (Inspra) product package insert.  Pfizer Inc., Ney York, NY.  April 2008.
    2. Jackson 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. 2006:759-762.
    3. Karim A.  Spironolactone: disposition, metabolism, pharmacodynamics and bioavailability.  Drug Metab Rev  1978;8:151-88.
    4. Sherry 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.
    5. Rendic 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.
    6. United 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.
    7. Ohno 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  2007;46:681-96.
    8. Pitt 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.

MESH Terms & Keywords

  • Eplerenone, Inspra, Aldactone, Spironolactone, Aldosterone Antagonists, Eplerenone Drug Interactions