Clinical pharmacokinetics of digitoxin

D. Perrier, Michael Mayersohn, F. I. Marcus

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The disposition kinetics of digitoxin have not been as thoroughly examined as those of digoxin. Digitoxin appears to be rapidly and completely absorbed after oral or intramuscular administration although there have been no estimates of absolute bioavailability. There is only one study that has examined the relative bioavailability of two commercial digitoxin tablets (USA) and no differences were found other than in rates of absorption. The near identical responses produced by equal oral and intravenous doses of digitoxin support the suggestion of completeness of absorption. The digitoxin plasma concentration-time curve seems to be adequately described by a two compartment open model, although such data have not been rigorously analyzed. Distribution is complete within 4 to 6 hr and response is not associated with plasma concentrations during the distributive phase, suggesting that the site of action resides in a tissue compartment of a multi-compartment pharmacokinetic model. Digitoxin is strongly bound (>90%) to plasma protein (albumin) with an association constant of 9.62 x 104 litre/mole. The volume of distribution of digitoxin is approximately 0.6 L/kg, although estimates vary considerably. This volume is much smaller than digoxin, consistent with the great plasma protein binding of digitoxin. As with the estimation of the other pharmacokinetic parameters of digitoxin, estimates of elimination vary greatly, primarily as a result of differences in assay methods. Digitoxin is eliminated by hepatic metabolism and as unchanged drug in the urine and feces. Metabolism is considered to be the major route of elimination, accounting for about 70% of a dose. While most reports indicate that only 30% of a digitoxin dose is eliminated intact (in urine and feces) this value may be as high as 48%. Digitoxin elimination appears to be independent of dose and route of administration, although there is substantial inter-patient variation in elimination half-life. Half-lives range from 2.4 to 16.4 days with a mean value of approximately 7.6 days. The shortest mean half-life (4.8 days) was observed with the most specific assay and the longest mean half-life (9.8 days) with the least specific method. Renal insufficiency has been reported to result in either decreased or increased digitoxin elimination. While elimination may be expected to increase if plasma protein binding is reduced, there are conflicting reports on the influence of renal insufficiency on digitoxin binding. Part of this conflict may be resolved with the observation that patients undergoing hemodialysis and who receive heparin have a greater fraction of free digitoxin in plasma soon after heparin administration. It appears that plasma free fatty acid concentrations increase in response to heparin which in turn competes with digitoxin for albumin binding sites. Digitoxin half-life is reported to be shortened and volume of distribution increased in nephrotic patients. The influence of hepatic impairment on digitoxin elimination has not been thoroughly examined and there is only one report suggesting reduced elimination in this situation. Cholestyramine has been shown to reduce digitoxin half-life by interfering with the enterohepatic recycling of the drug. There have been no reports to indicate that other drugs may displace digitoxin from plasma protein binding sites. Concurrent administration of phenylbutazone, phenobarbitone, and phenytoin decreases digitoxin plasma concentrations; presumably by inducing digitoxin metabolism. Phenobarbitone, rifampicin and spironolactone have been reported to decrease digitoxin half-life. Numerous studies have attempted to better define the therapeutic plasma concentration range of digitoxin. Plasma concentrations greater than 35 to 40 ng/ml are generally considered to be associated with potential toxicity while concentrations from 15 to 25 ng/ml are considered to be within the therapeutic range. As with digitoxin there is considerable variation and overlap in plasma concentrations associated with toxicity and therapeutic response.

Original languageEnglish (US)
Pages (from-to)292-311
Number of pages20
JournalClinical Pharmacokinetics
Volume2
Issue number4
StatePublished - 1977

Fingerprint

Digitoxin
Pharmacokinetics
Half-Life
Blood Proteins
Protein Binding
Heparin
Digoxin
Phenobarbital
Feces
Biological Availability
Renal Insufficiency

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Perrier, D., Mayersohn, M., & Marcus, F. I. (1977). Clinical pharmacokinetics of digitoxin. Clinical Pharmacokinetics, 2(4), 292-311.

Clinical pharmacokinetics of digitoxin. / Perrier, D.; Mayersohn, Michael; Marcus, F. I.

In: Clinical Pharmacokinetics, Vol. 2, No. 4, 1977, p. 292-311.

Research output: Contribution to journalArticle

Perrier, D, Mayersohn, M & Marcus, FI 1977, 'Clinical pharmacokinetics of digitoxin', Clinical Pharmacokinetics, vol. 2, no. 4, pp. 292-311.
Perrier, D. ; Mayersohn, Michael ; Marcus, F. I. / Clinical pharmacokinetics of digitoxin. In: Clinical Pharmacokinetics. 1977 ; Vol. 2, No. 4. pp. 292-311.
@article{bcf59ff360be4ad4883958ea189ada18,
title = "Clinical pharmacokinetics of digitoxin",
abstract = "The disposition kinetics of digitoxin have not been as thoroughly examined as those of digoxin. Digitoxin appears to be rapidly and completely absorbed after oral or intramuscular administration although there have been no estimates of absolute bioavailability. There is only one study that has examined the relative bioavailability of two commercial digitoxin tablets (USA) and no differences were found other than in rates of absorption. The near identical responses produced by equal oral and intravenous doses of digitoxin support the suggestion of completeness of absorption. The digitoxin plasma concentration-time curve seems to be adequately described by a two compartment open model, although such data have not been rigorously analyzed. Distribution is complete within 4 to 6 hr and response is not associated with plasma concentrations during the distributive phase, suggesting that the site of action resides in a tissue compartment of a multi-compartment pharmacokinetic model. Digitoxin is strongly bound (>90{\%}) to plasma protein (albumin) with an association constant of 9.62 x 104 litre/mole. The volume of distribution of digitoxin is approximately 0.6 L/kg, although estimates vary considerably. This volume is much smaller than digoxin, consistent with the great plasma protein binding of digitoxin. As with the estimation of the other pharmacokinetic parameters of digitoxin, estimates of elimination vary greatly, primarily as a result of differences in assay methods. Digitoxin is eliminated by hepatic metabolism and as unchanged drug in the urine and feces. Metabolism is considered to be the major route of elimination, accounting for about 70{\%} of a dose. While most reports indicate that only 30{\%} of a digitoxin dose is eliminated intact (in urine and feces) this value may be as high as 48{\%}. Digitoxin elimination appears to be independent of dose and route of administration, although there is substantial inter-patient variation in elimination half-life. Half-lives range from 2.4 to 16.4 days with a mean value of approximately 7.6 days. The shortest mean half-life (4.8 days) was observed with the most specific assay and the longest mean half-life (9.8 days) with the least specific method. Renal insufficiency has been reported to result in either decreased or increased digitoxin elimination. While elimination may be expected to increase if plasma protein binding is reduced, there are conflicting reports on the influence of renal insufficiency on digitoxin binding. Part of this conflict may be resolved with the observation that patients undergoing hemodialysis and who receive heparin have a greater fraction of free digitoxin in plasma soon after heparin administration. It appears that plasma free fatty acid concentrations increase in response to heparin which in turn competes with digitoxin for albumin binding sites. Digitoxin half-life is reported to be shortened and volume of distribution increased in nephrotic patients. The influence of hepatic impairment on digitoxin elimination has not been thoroughly examined and there is only one report suggesting reduced elimination in this situation. Cholestyramine has been shown to reduce digitoxin half-life by interfering with the enterohepatic recycling of the drug. There have been no reports to indicate that other drugs may displace digitoxin from plasma protein binding sites. Concurrent administration of phenylbutazone, phenobarbitone, and phenytoin decreases digitoxin plasma concentrations; presumably by inducing digitoxin metabolism. Phenobarbitone, rifampicin and spironolactone have been reported to decrease digitoxin half-life. Numerous studies have attempted to better define the therapeutic plasma concentration range of digitoxin. Plasma concentrations greater than 35 to 40 ng/ml are generally considered to be associated with potential toxicity while concentrations from 15 to 25 ng/ml are considered to be within the therapeutic range. As with digitoxin there is considerable variation and overlap in plasma concentrations associated with toxicity and therapeutic response.",
author = "D. Perrier and Michael Mayersohn and Marcus, {F. I.}",
year = "1977",
language = "English (US)",
volume = "2",
pages = "292--311",
journal = "Clinical Pharmacokinetics",
issn = "0312-5963",
publisher = "Adis International Ltd",
number = "4",

}

TY - JOUR

T1 - Clinical pharmacokinetics of digitoxin

AU - Perrier, D.

AU - Mayersohn, Michael

AU - Marcus, F. I.

PY - 1977

Y1 - 1977

N2 - The disposition kinetics of digitoxin have not been as thoroughly examined as those of digoxin. Digitoxin appears to be rapidly and completely absorbed after oral or intramuscular administration although there have been no estimates of absolute bioavailability. There is only one study that has examined the relative bioavailability of two commercial digitoxin tablets (USA) and no differences were found other than in rates of absorption. The near identical responses produced by equal oral and intravenous doses of digitoxin support the suggestion of completeness of absorption. The digitoxin plasma concentration-time curve seems to be adequately described by a two compartment open model, although such data have not been rigorously analyzed. Distribution is complete within 4 to 6 hr and response is not associated with plasma concentrations during the distributive phase, suggesting that the site of action resides in a tissue compartment of a multi-compartment pharmacokinetic model. Digitoxin is strongly bound (>90%) to plasma protein (albumin) with an association constant of 9.62 x 104 litre/mole. The volume of distribution of digitoxin is approximately 0.6 L/kg, although estimates vary considerably. This volume is much smaller than digoxin, consistent with the great plasma protein binding of digitoxin. As with the estimation of the other pharmacokinetic parameters of digitoxin, estimates of elimination vary greatly, primarily as a result of differences in assay methods. Digitoxin is eliminated by hepatic metabolism and as unchanged drug in the urine and feces. Metabolism is considered to be the major route of elimination, accounting for about 70% of a dose. While most reports indicate that only 30% of a digitoxin dose is eliminated intact (in urine and feces) this value may be as high as 48%. Digitoxin elimination appears to be independent of dose and route of administration, although there is substantial inter-patient variation in elimination half-life. Half-lives range from 2.4 to 16.4 days with a mean value of approximately 7.6 days. The shortest mean half-life (4.8 days) was observed with the most specific assay and the longest mean half-life (9.8 days) with the least specific method. Renal insufficiency has been reported to result in either decreased or increased digitoxin elimination. While elimination may be expected to increase if plasma protein binding is reduced, there are conflicting reports on the influence of renal insufficiency on digitoxin binding. Part of this conflict may be resolved with the observation that patients undergoing hemodialysis and who receive heparin have a greater fraction of free digitoxin in plasma soon after heparin administration. It appears that plasma free fatty acid concentrations increase in response to heparin which in turn competes with digitoxin for albumin binding sites. Digitoxin half-life is reported to be shortened and volume of distribution increased in nephrotic patients. The influence of hepatic impairment on digitoxin elimination has not been thoroughly examined and there is only one report suggesting reduced elimination in this situation. Cholestyramine has been shown to reduce digitoxin half-life by interfering with the enterohepatic recycling of the drug. There have been no reports to indicate that other drugs may displace digitoxin from plasma protein binding sites. Concurrent administration of phenylbutazone, phenobarbitone, and phenytoin decreases digitoxin plasma concentrations; presumably by inducing digitoxin metabolism. Phenobarbitone, rifampicin and spironolactone have been reported to decrease digitoxin half-life. Numerous studies have attempted to better define the therapeutic plasma concentration range of digitoxin. Plasma concentrations greater than 35 to 40 ng/ml are generally considered to be associated with potential toxicity while concentrations from 15 to 25 ng/ml are considered to be within the therapeutic range. As with digitoxin there is considerable variation and overlap in plasma concentrations associated with toxicity and therapeutic response.

AB - The disposition kinetics of digitoxin have not been as thoroughly examined as those of digoxin. Digitoxin appears to be rapidly and completely absorbed after oral or intramuscular administration although there have been no estimates of absolute bioavailability. There is only one study that has examined the relative bioavailability of two commercial digitoxin tablets (USA) and no differences were found other than in rates of absorption. The near identical responses produced by equal oral and intravenous doses of digitoxin support the suggestion of completeness of absorption. The digitoxin plasma concentration-time curve seems to be adequately described by a two compartment open model, although such data have not been rigorously analyzed. Distribution is complete within 4 to 6 hr and response is not associated with plasma concentrations during the distributive phase, suggesting that the site of action resides in a tissue compartment of a multi-compartment pharmacokinetic model. Digitoxin is strongly bound (>90%) to plasma protein (albumin) with an association constant of 9.62 x 104 litre/mole. The volume of distribution of digitoxin is approximately 0.6 L/kg, although estimates vary considerably. This volume is much smaller than digoxin, consistent with the great plasma protein binding of digitoxin. As with the estimation of the other pharmacokinetic parameters of digitoxin, estimates of elimination vary greatly, primarily as a result of differences in assay methods. Digitoxin is eliminated by hepatic metabolism and as unchanged drug in the urine and feces. Metabolism is considered to be the major route of elimination, accounting for about 70% of a dose. While most reports indicate that only 30% of a digitoxin dose is eliminated intact (in urine and feces) this value may be as high as 48%. Digitoxin elimination appears to be independent of dose and route of administration, although there is substantial inter-patient variation in elimination half-life. Half-lives range from 2.4 to 16.4 days with a mean value of approximately 7.6 days. The shortest mean half-life (4.8 days) was observed with the most specific assay and the longest mean half-life (9.8 days) with the least specific method. Renal insufficiency has been reported to result in either decreased or increased digitoxin elimination. While elimination may be expected to increase if plasma protein binding is reduced, there are conflicting reports on the influence of renal insufficiency on digitoxin binding. Part of this conflict may be resolved with the observation that patients undergoing hemodialysis and who receive heparin have a greater fraction of free digitoxin in plasma soon after heparin administration. It appears that plasma free fatty acid concentrations increase in response to heparin which in turn competes with digitoxin for albumin binding sites. Digitoxin half-life is reported to be shortened and volume of distribution increased in nephrotic patients. The influence of hepatic impairment on digitoxin elimination has not been thoroughly examined and there is only one report suggesting reduced elimination in this situation. Cholestyramine has been shown to reduce digitoxin half-life by interfering with the enterohepatic recycling of the drug. There have been no reports to indicate that other drugs may displace digitoxin from plasma protein binding sites. Concurrent administration of phenylbutazone, phenobarbitone, and phenytoin decreases digitoxin plasma concentrations; presumably by inducing digitoxin metabolism. Phenobarbitone, rifampicin and spironolactone have been reported to decrease digitoxin half-life. Numerous studies have attempted to better define the therapeutic plasma concentration range of digitoxin. Plasma concentrations greater than 35 to 40 ng/ml are generally considered to be associated with potential toxicity while concentrations from 15 to 25 ng/ml are considered to be within the therapeutic range. As with digitoxin there is considerable variation and overlap in plasma concentrations associated with toxicity and therapeutic response.

UR - http://www.scopus.com/inward/record.url?scp=0017725282&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0017725282&partnerID=8YFLogxK

M3 - Article

VL - 2

SP - 292

EP - 311

JO - Clinical Pharmacokinetics

JF - Clinical Pharmacokinetics

SN - 0312-5963

IS - 4

ER -