Studies on digitalis; X. Digitoxin metabolites in human myocardium and relationship between myocardial and serum concentrations of digitoxin in patients on maintenance treatment

Storstein, Liv

doi:10.1002/cpt1977214395

Cited by 16 publications

(6 citation statements)

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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%

“…It is even more complicated with regard to digitoxin which has few metabolites. According to Storstein et al [108] digitoxin accounts for only half of the cardioactive substances in the myocardium. The mean myocardial and serum concentrations ratio for digitoxin from the study was 5.4 (range: 1.1-38.0).…”

Section: Cardiac Pharmaceutical Agentsmentioning

confidence: 99%

“…After being corrected for serum protein binding the calculated ratio was 200. It is noteworthy that after such correction, the ratio for digoxin stands at 100, indicating that digitoxin had a higher affinity for myocardial tissue [108].…”

Section: Cardiac Pharmaceutical Agentsmentioning

confidence: 99%

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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%

Section: Cardiac Pharmaceutical Agentsmentioning

confidence: 99%

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

Tylutki

Polak

2015

Biopharm & Drug Disp

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“…A high mean ratio of 2.94 was found when free drug concentration was used for the calculations. As discussed in a previous paper free digitoxin concentrations are also more relevant for uptake in the myocardium (42). Myocardial/free digitoxin serum concentration ratio was around 200 compared to 100 for digoxin.…”

Section: Blood-brain Barrier For Digitalis Glycosides In Humansmentioning

confidence: 66%

Studies on digitalis. 23. Blood‐brain barrier of digitoxin in humans

Storstein¹,

Nore²,

Sjaastad³

1979

Clinical Cardiology

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Summary: Data on the cerebrospinal fluid concentrations of digitoxin in man have been lacking. Aim of the present study was to investigate serum and cerebrospinal fluid concentrations of digitoxin. Eleven patients with normal cerebrospinal fluid composition, normal serum albumin values, normal renal and hepatic function and normal hematologic tests were given a single dose of 0.6 mg digitoxin. Serum and cerebrospinal fluid were collected 16 h after the dose, and assayed by radio-immunoassay, serum digitoxin protein binding was measured with equilibrium dialysis.Mean serum digitoxin concentration was 12.4 ng/ml (SO 2.6) and mean CSF concentration 0.84 ngiml (SO 0.22) giving a CSF/serum ratio of 0.07 (SO 0.03). Serum digitoxin protein binding was 97.4% (SO 0.4) and the calculated CSF/free serum digitoxin ratio was thus 2.94 (SO 1.43).Free serum digitoxin concentrations are more relevant for pharmacologic effect than total serum digitoxin concentrations and also for passage into the central nervous system. Using free drug concentrations the ratio between digitoxin in serum and CSF is lower than reported values for digoxin indicating a higher penetrance of digitoxin into the central nervous system. This corresponds well with the higher lipid solubility of digitoxin. Post mortem studies have shown that concentrations are higher in cerebral tissue than in CSF for digoxin. Determination of CSF concentrations thus probably underestimates the penetrance of digitalis glycosides into the central nervous system, but may serve as a useful indicator of variance among digitalis glycosides.

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“…37 The data are not comparable with the results of this study because kinetic aspects are important, as will be discussed in a separate paper. 53 Findings in serum and urine 24 hr after the dose are in good accordance, but the agreement is not so elose as for the steady-state group. Digitoxin is mainly excreted unchanged with DG-3 as its main metabolite.…”

Section: Some Aspects Of Digitalis Metabolism Mostmentioning

confidence: 79%

Studies on digitalis; VIII. Digitoxin metabolism on a maintenance regimen and after a single dose

Storstein

1977

Clin Pharma and Therapeutics

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The metabolic pattern of cardioactive and inactive conjugated metabolites of digitoxin on maintenance (9 patients) and after a single 0.6-mg dose (5 patients) was studied in patients with normal renal and hepatic function. Serum samples were obtained 24 hr after the last dose, and urine was collected over 24 hr. The extent of conjugation to glucuronic and sulfuric acid was 35.0% (SD, 17.4) in whole serum and 31.6% (SD, 19.3) in urine samples. Unchanged digitoxin was the main cardioactive substance found both in serum and in urine (89.7% and 87.0%) in the steady-state group. All known cardioactive metabolites were present; digoxin represented less than 1%. All active metabolites were conjugated to glucuronic/sulfuric acid. Serum and urine patterns of metabolites were quite similar, Hydrolysis and conjugation appeared to be more important pathways than hydroxylation. Unchanged digitoxin was the most important cardioactive substance in serum and urine (80.4% and 56.5%) in the single-dose group. Digoxin was the main cardioactive metabolite (12.5% in serum and 25.5% in urine). All active metabolites were conjugated. Hydroxylation, hydrolysis, and conjugation seemed to be equally important. The most important differences between the steady-state and single-dose groups were that in the steady-state group there was significantly more unchanged digitoxin, far less digoxin, and less hydroxylated metabolities than in the single-dose group. Caution is thus necessary when interpreting single-dose data for a drug that is used for maintenance.

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Studies on digitalis; X. Digitoxin metabolites in human myocardium and relationship between myocardial and serum concentrations of digitoxin in patients on maintenance treatment

Cited by 16 publications

References 9 publications

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

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

Studies on digitalis. 23. Blood‐brain barrier of digitoxin in humans

Studies on digitalis; VIII. Digitoxin metabolism on a maintenance regimen and after a single dose

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