Intoxication due to negative canrenone interference in digoxin drug monitoring

doi:10.1016/S0140-6736(99)03818-0

The Lancet

Volume 354, Issue 9185, 2 October 1999, Pages 1176-1177

https://doi.org/10.1016/S0140-6736(99)03818-0 Get rights and content

Summary

Canrenone and spironolactone caused falsely low readings in a common assay for digoxin (AxSym MEIA) due to negative cross-reactivity. Misleading subtarget concentrations were repeatedly reported, and falsely guided drug dosing resulted in a case of digoxin intoxication.

References (5)

SA Jortani et al.
Digoxin and its related endogenous factors
Crit Rev Clin Lab Sci
(1997)
RA Pleasants et al.
Reassessment of cross-reactivity of spironolactone metabolites with four digoxin immunoassays
Ther Drug Monit
(1989)

There are more references available in the full text version of this article.

Cited by (42)

Immunoassays for therapeutic drug monitoring and clinical toxicology
2020, Handbook of Analytical Separations
Citation Excerpt :
Cross-reactivity can lead to either falsely elevated or decreased results, depending on the assay format. A good example of this is in the case of digoxin monitoring where digoxin-like immunoreactive substances (DLISs) and digitoxin-like immunoreactive substances (DTLISs) have been shown to produce falsely elevated results with FPIA [55]; but coronene and spironolactone have demonstrated the ability to produce falsely low results for digoxin when using an MEIA format [56]. A recent development is the adaptation of immunoassay formats to develop testing outside the clinical laboratory, specifically for point-of-care testing (POCT).
Immunoassays are quantitative analytical methods that make use of antibodies as reagents. The highly specific binding and large association constants (K_a) of antibodies make them useful for detection and quantitation of analytes in complex sample matrices such as body fluids including blood, urine, saliva, sweat, or vitreous humor. Methods based on immunochemical reactions are some of the most sensitive and specific assays available to laboratorians. Many formats of immunoassays have been automated and are widely used in the clinical laboratory for therapeutic drug monitoring (TDM).
Model analysis of bidirectional interference in two-stage labeled-ligand immunoassays
2017, Clinical Biochemistry
Citation Excerpt :
The negative interference in the MEIA was found to be due to canrenone, a metabolite of potassium canrenoate which was also administered to the patient. Digoxin toxicity in the patient was a consequence of the misinformation regarding digoxin concentration due to interference in the digoxin assay, indicating the significant clinical impact of such negative interference [14]. Whereas a model rendition of assay characteristics is useful to understand, the practical model applications per se are limited.
Immunoassays involving sample incubation followed by a wash step prior to introduction of labeled analyte are potentially subject to both positive and negative interference (bidirectional interference) by a competing ligand. We examine this phenomenon from a theoretical standpoint using a mathematical model for sequential-step immunoassays in the presence of interferent.
Competitive binding to antibody between analyte and interferent was modeled for sequential-step immunoassays. A primary assumption was that the ratio of affinity constants between the intended analyte and the interferent reflected the ratio of dissociation rate constants, with the higher dissociation rate constant for the lesser affinity ligand.
Relationships of parameters (relative affinity constants, relative concentrations) for analyte and interferent were determined for conditions in which bidirectional interference can occur, for both steady-state and non-steady-state sample incubation conditions. Non-steady state sample incubation conditions can enhance the effects of an interferent. Homogeneous assay formats utilizing labeled ligand without a wash step can also demonstrate bidirectional interference, but positive interference is favored under such formats.
Model calculations demonstrate the theoretical basis for bidirectional interference in two-stage immunoassays. Results delineate constraints on conditions in which bidirectional interference can occur.
Immunoassays and Issues With Interference in Therapeutic Drug Monitoring
2016, Clinical Challenges in Therapeutic Drug Monitoring: Special Populations, Physiological Conditions, and Pharmacogenomics
Immunoassays are widely used for therapeutic drug monitoring (TDM), but they are also subject to interferences. In general, digoxin immunoassays are mostly affected (endogenous digoxin-like immunoreactive substances, digoxin metabolites, spironolactone, Digibind, and DigiFab, as well as ceratin herbal supplements). In addition, interference of carbamazepine-10,11-epoxide in carbamazepine immunoassays may have clinical significance. Hydroxyzine and cetirizine interfere with particle-enhanced turbidimetric inhibition immunoassay. Various drugs affect immunoassays for tricyclic antidepressants. This chapter covers all such interferences in TDM.
Challenges in Therapeutic Drug Monitoring of Digoxin and Other Anti-Arrhythmic Drugs
2012, Therapeutic Drug Monitoring: Newer Drugs and Biomarkers
Challenges in Therapeutic Drug Monitoring of Digoxin and Other Anti-Arrhythmic Drugs
2012, Therapeutic Drug Monitoring
Canrenone
2008, xPharm: The Comprehensive Pharmacology Reference

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Research LettersIntoxication due to negative canrenone interference in digoxin drug monitoring

Summary

Digoxin and its related endogenous factors

Crit Rev Clin Lab Sci

Reassessment of cross-reactivity of spironolactone metabolites with four digoxin immunoassays

Ther Drug Monit

Research Letters
Intoxication due to negative canrenone interference in digoxin drug monitoring