Interference of spironolactone potassium canrenoate and canrenone in digoxin assays

Spironolactone, a competitive aldosterone antagonist, has been used clinically in the therapy of hypertension and congestive heart failure for a long time. Spironolactone is rapidly and extensively metabolized, and its metabolite canrenone is also pharmacologically active. Spironolactone and canrenone have structural similarity with digoxin (Fig. 1). Although not in formulary in the USA, potassium canrenoate is used in Europe and other countries. Potassium canrenoate is also metabolized to canrenone.

Because spironolactone and digoxin may be used concurrently in the patient management, interference of spironolactone and canrenone in therapeutic monitoring of digoxin is troublesome. Positive interference of spironolactone and its active metabolite canrenone in the RIA for digoxin has been reported as early as 1974 (67). Potassium canrenoate also showed positive interference with serum digoxin monitoring by both RIA and enzyme immunoassay (68,69). Morris et al. (70) reported positive interference of spironolactone in digoxin measurement using the FPIA. Later, other authors verified the interference of spironolactone and canrenone in the FPIA and other commonly used immunoassays for digoxin (71,72). Okazaki et al. also reported falsely elevated digoxin levels in patients receiving digoxin and potassium canrenoate. The authors reported two cases where cross-reactivity of the assay system caused clinical problem and recommended use of the OPUS digoxin assay, which showed minimum cross-reactivity (73).

(C18H31O9)O

(C18H31O9)O

Digoxin

Spironolactone

Digoxin

Spironolactone

(C7H13O3P

Oleandrin

Bufalin

Fig. 1. Chemical Structure of Digoxin, Spironolactone, Oleandrin and Bufalin.

Oleandrin

Bufalin

Fig. 1. Chemical Structure of Digoxin, Spironolactone, Oleandrin and Bufalin.

Steimer et al. reported negative interference of canrenone in digoxin measurement. Canrenone and spironolactone caused falsely low digoxin values because of negative interference in serum digoxin measurement when a MEIA for digoxin was used. Misleading sub-therapeutic concentrations of digoxin as measured on several occasions led to falsely guided digoxin dosing resulting in serious digoxin toxicity in the patients (74).

Interference of spironolactone, potassium canrenoate, and their common metabolite canrenone may be positive or negative in serum digoxin measurement using immunoassays. Spironolactone and its metabolite canrenone can falsely elevate serum digoxin levels if measured using FPIA, ACA, or Elecsys (positive interference) or falsely lower digoxin levels if measured by MEIA, Imx, and Dimension (negative interference). The magnitude of interference is more significant with potassium canrenoate where concentration of its metabolite canrenone can be significantly higher. In one report, authors observed a 42% decline in expected value of serum digoxin in the presence of 3125 ng/mL of canrenoate using MEIA, 78% decline in using Dimension and 51% decrease using IMx. A positive bias was observed with the ACA (0.7 ng/mL), TDx (0.62 ng/mL), and Elessys (0.58 ng/mL). EMIT 2000, and the Vitros digoxin assay, is free from such interference (75).

Our experience is that Bayer's Chemiluminescent digoxin assay is also free from such interference. Moreover, interference of spironolactone and its metabolite canrenone can be mostly eliminated by ultrafiltration because both compounds are strongly protein bound. However, in the case of therapy with K-canrenoate (not used in the USA), complete elimination of this interference in certain digoxin assays cannot be achieved because of higher concentrations of K-canrenoate and higher concentrations of its metabolite canrenone observed in plasma (76). Howard et al. (77) demonstrated that low-dose spironolactone (up to 25 mg per day) as used for oral therapy does not cause clinically significant negative interference in the MEIA digoxin assay on the AxSYM analyzer by comparing results with the EMIT assay which is free from spironolactone interference. However, with a higher spironolactone dose, such as 200 mg per day, a significant interference may be observed with the MEIA (78).

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