Physiological Distribution of Digoxin in Human Heart

Coltart, D J; Güllner, Hans-Georg; Billingham, M. E.; Goldman, Robert H.; Stinson, Edward B.; Kalman, Sumner M.; Harrison, David

doi:10.1136/bmj.4.5947.733

Cited by 29 publications

(12 citation statements)

References 8 publications

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“…The predominant role in taking up digoxin molecules is said to be played by myocardial cells rather than by connective tissue and fat [106]. A direct relationship between digoxin concentration in plasma and concentration in the heart cell microsomal fraction was found [107], since the latter may be related to the inotropic effect [108]. However, the total levels in the myocardium were also widely investigated.…”

Section: Cardiac Pharmaceutical Agentsmentioning

confidence: 99%

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Tylutki

Polak

2015

Biopharm & Drug Disp

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ABSTRACT:Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart.

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Section: Cardiac Pharmaceutical Agentsmentioning

confidence: 99%

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Tylutki

Polak

2015

Biopharm & Drug Disp

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“…Cardiac transplantation has afforded a very special opportunity to study the distribution of digoxin in the human heart because samples from the recipient's organ can be analysed with both the timing of the last digoxin dose known and a plasma sample taken after induction of anaesthesia, and before cardiopulmonary bypass. In such a study of 7 transplant recipients' hearts, Coltart et al (1974) found no consistent relation between plasma concentrations and tissue concentrations of digoxin in samples from each of the cardiac chambers. Moreover, in the presence of diffuse histological abnormalities of the myocardium, tissue digoxin was decreased and such structural inhomogeneity seemed at least partly to account for disparities in tissue concentrations within individual hearts.…”

mentioning

confidence: 92%

“…In recipients' hearts removed at cardiac transplantation, Coltart et al (1974) found that in the presence of diffuse histological abnormalities of the myocardium, tissue digoxin concentrations were decreased, but in 3 hearts microsomal fraction digoxin concentrations in samples from various parts of the heart were uniform. Thus, the inhomogeneity of tissue digoxin concentrations in these diseased and malfunctioning hearts is not paralleled by site-to-site disparities of microsomally bound digoxin and this presumably reflects uniformity of binding to the possible receptor site.…”

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confidence: 97%

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Relation between concentrations of digoxin in the myocardium and in the plasma.

Malcolm¹,

Coltart²

1977

Heart

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It soon becomes apparent to those who use cardiac glycosides clinically that the relation between the amount of drug administered and the therapeutic effect is highly variable. The correlation of dose and effect of the drug is influenced by a number of factors including bioavailability, completeness of absorption, apparent volume of distribution, rate of elimination, degree of plasma protein binding, diffusion and active transport to the site of action, and local factors at the side of action (Koch-Weser, 1972;Sjoqvist and Bertilsson, 1973). KochWeser (1972) effect depended on the drug itself and not on metabolites, (2) protein binding was minimal, (3) the concentration/response graph followed a known and readily definable form such as the linear or monoexponential, and (4) the functional state of the drug receptor responded predictably and instantaneously, or nearly so, to changes in plasma concentration. The first condition is satisfied by digoxin but the second and third conditions are only partially satisfied, and the fourth is not. The importance of the second and third points is crucial and may be illustrated by recourse to the conceptual device of mathematical modelling. The simplest practical model to consider in this situation is the two-compartment model first comprehensively described by Teorell in 1937(Vere, 1972. Administered drug rapidly enters a 'space' where thorough mixing soon occurs (first compartment f blood and some part of well-perfused tissues) and thereafter exchanges with a 'space' more remote from the outside world by virtue of relatively slower ingress and egress of drug across the intercompartmental boundary (second compartment t cells and most drug receptor sites). Intercompartmental transfer is treated as a two-way flux, and absorption and elimination of the drug as one-way fluxes according to the Fick equations for simple diffusion, a valid approach simply because most drugs are effectively non-electric in their transfer behaviour. Teorell showed that very soon after full absorption of a drug, all the terms in the mathematical description of the fluxes across the various boundaries become vanishingly small except for the one-way flux of drug removal from tissue. This leaves a single exponential for removal of drug from the blood and so, unless blood volume alters, plasma concentrations of the drug should follow this exponential form (Vere, 1972).

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“…Relationships between drug response and digoxin concentrations in blood, myocardium and receptor site are becoming more clearly defined [17,42,51,52] and there is a consensus of opinion that the serum digoxin concentra tion provides an useful aid in achieving therapeutic doses. Although appre ciable overlap between toxic and nontoxic levels has been the usual experience, mean serum concentrations in a number of series are about twofold higher in patients with cardiac disease who had evidence of toxicity than in those without such evidence [17] (fig.…”

Section: Therapeutic Range O F Sdcmentioning

confidence: 99%