Digoxin and Its Related Endogenous Factors

Abstract

The digitalis drugs are plant-derived cardenolide compounds used medicinally for several hundred years. These drugs elicit inotropic and chronotropic effects on the heart, but they also affect many other tissues. The mechanism of action involves inhibition of the ion-transport activity of a membrane-associated protein called Na, K-ATPase (sodium pump). Present theory holds that the sodium pump is the principal molecular receptor for the digitalis drugs. Recent evidence indicates the presence of naturally occurring digitalis-like compounds in mammals. It is believed these compounds, collectively known as either digitalis-like (DLF) or ouabain-like (OLF) factors, may be endogenous hormones regulating the biological activity of the sodium pump and its isoforms. The presence of deglycosylated and other congeners of one specific DLF, the digoxin-like immunoreactive factor (DLIF), has very recently been described in humans. Digoxin as a drug is the most widely prescribed digitalis in the U.S., and its measurement in serum has established a model for present-day therapeutic drug monitoring (TDM). Historically, the accurate measurement of digoxin in blood has been difficult. This article focuses on the present understanding of the clinical use of digoxin, factors that affect the accuracy of measuring digoxin, the principle of measuring metabolically active species of digoxin, and the effects of DLIF and other interfering substances in digoxin immunoassay.

Lack of Pharmacokinetic Interaction between Gemifloxacin and Digoxin in Healthy Elderly Volunteers

“…An independent determination of digoxin concentration was performed using radioimmunoassay, and this revealed a digoxin level below 0.5 ng/ml. This falsely high digoxin level was thought to be due to the presence of a 'digoxin-like' immunoreactive factor, a condition that occurs only rarely [8]. Thus, only the 14 subjects who completed all dosing sessions were included in the pharmacokinetic evaluation.…”

Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules

“…The identification and characterization of the circulating Na C /K C ATPase antagonist remained elusive for a long time. After painstaking research spanning three decades, two groups independently identified the circulating factor(s) as substances similar to plant-derived ouabain and digoxin that are synthesized in the mammalian adrenal glands (Hamlyn et al 1982, 1991, Craver & Valdes 1983, Graves et al 1983, Valdes 1985a,b,c, Valdes et al 1985, Skogen et al 1987, Lackner et al 1988, Siegfried & Valdes 1988, Shaikh et al 1991, Qazzaz & Valdes 1996, Qazzaz et al 1996a,b, 2000, Ferrandi et al 1997, Jortani & Valdes 1997, Perrin et al 1997, Grider et al 1999, Manunta et al 2001a,b, Pierdomenico et al 2001, el-Masri et al 2002, El-Mallakh et al 2007). Bagrov and colleagues identified the presence of endogenous bufadienolides, marinobufagenin, and telocinobufagin, in plasma of rats with renal failure, diabetes, and preeclampsia, and in plasma from patients with congestive heart failure and renal failure (Bagrov et al 1996, 2005, 2005a,b, 2010a,b, 2012, Gonick et al 1998, Lopatin et al 1999 Effects of low nanomolar to picomolar concentrations of ouabain on Na…”

Strategies for Developing Biomarkers of Heart Failure

“…In this as well as in other volume-overload conditions, such as pregnancy and renal or hepatic impairment, plasma concentrations of cardenolides have been shown to be increased (53 ). Endogenous mammalian cardenolides are thought to be effector ligands that regulate the sodium pump as a receptor.…”

“…Increased concentrations of endogenous cardenolides, both DLIF and OLF, have been reported in various pathologic conditions such as renal failure, liver failure, hypertension, and HF, as well as in physiologic conditions such as pregnancy (53 ). The common feature of these conditions is the state of hypervolemia.…”