The pharmacokinetics of digitalis glycosides have been the subject of extensive re­ view (IISALO, 1977; ARONSON, 1980; PERRIER et ai., 1977). Research on glycoside kinetics has progressed at a rapid pace, requiring continuing reevaluation of the state of our understanding of this problem. The present article focuses on the effect of disease states (renal, gastrointestinal, thyroid, and cardiac) on the absorption, distribution, and clearance of a number of digitalis glycosides. Evidence is critically reviewed, and interpreted with respect to possible clinical implications. A. Renal Insufficiency I. Strophanthin Strophanthin disposition in renal failure has been evaluated in only two studies. KRAMER et ai. (1970) determined an elimination half-life of 14 h in normals as com­ pared to 60 h in anuric patients. Similar results were reported by BRASS and Pm­ LIPPS (1970) using tritiated strophanthin. They found a half-life value of 18 h in healthy individuals as compared to 68 h in anuric patients. The findings clearly in­ dicate that the elimination half-life of strophanthin is prolonged in renal failure.

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Pharmacokinetics - Distribution, Metabolism, and Elimination.- 1 Pharmacokinetics of Digitoxin.- A. Introduction.- B. Drug Uptake and Tissue Distribution.- I. Rate of Distribution and Distribution Half-Life.- II. Tissue Compartments and the Apparent Volume of Distribution.- III. Tissue Distribution.- IV. Passage Across Biologic Membranes.- 1. Blood-Brain Barrier.- 2. Placental Transfer.- C. Metabolism.- I. Basic Studies with Tissue Preparations and in Animals.- II. Single-Dose Studies in Humans.- III. Digitoxin Metabolism in Humans on Maintenance Treatment.- D. Enterohepatic Circulation.- E. Elimination and Excretion Pathways.- I. Serum Elimination Half-Life.- II. Serum Digitoxin Concentrations on Maintenance Treatment.- III. Excretion Pathways.- F. Modifications by Age.- I. Neonates, Infants, and Children.- II. Old Age.- G. Modifications by Disease States.- I. Gastrointestinal Disease.- II. Thyroid Disease.- III. Hepatic Disease.- IV. Renal Disease.- 1. Uremic Patients on Hemodialysis.- 2. Uremia Per Se.- 3. Nephrotic Syndrome.- H. Concluding Remarks.- References.- 2 Pharmacokinetics of Digoxin and Derivatives.- A. Tissue Distribution.- B. Apparent Distribution Volume.- C. Elimination.- I. Metabolism.- 1. Cleavage of Digitoxose Residues.- 2. Conjugation Reactions.- 3. Hydrogenation.- II. Excretion.- 1. Renal Excretion.- 2. Renal Excretion of Metabolites.- 3. Factors Influencing Renal Elimination.- 4. Extrarenal Excretion.- 5. Effect of Extrarenal Excretion on Bioavailability.- 6. Prediction of Digoxin Elimination.- 7. Acceleration of Digoxin Elimination.- References.- 3 Pharmacokinetics of Strophanthus Glycosides.- A. Introduction.- B. Enteral Absorption.- I. Human Investigations.- 1. Ouabain.- 2. Strophanthoside K.- 3. Cymarin.- 4. Cymarol.- 5. Helveticoside Derivatives.- II Animal Experiments.- 1. Ouabain.- 2. Strophanthoside K.- 3. Cymarin.- 4. Convallatoxin.- 5. Other Derivatives of Strophanthidin K.- C. Blood Level and Tissue Distribution.- I. Human Investigations.- 1. Ouabain.- 2. Strophanthoside K.- 3. Acetylstrophanthidin.- II. Animal Experiments.- 1. Ouabain.- 2. Strophanthoside K.- 3. Cymarin.- 4. Convallatoxin.- D. Metabolism.- I. Human Investigations and Animal Experiments.- 1. Ouabain.- 2. Strophanthidin K Derivatives.- E. Excretion.- I. Human Investigations.- 1. Ouabain.- 2. Strophanthoside K.- 3. Cymarin.- 4. Acetylstrophanthidin.- II Animal Experiments.- 1. Ouabain.- 2. Strophanthoside K.- 3. Cymarin.- 4. Acetylstrophanthidin.- 5. Dihydroouabain.- 6. Convallatoxin.- F. Conclusions.- References.- 4 Pharmacokinetics of Squill Glycosides.- A. Introduction.- B. Distribution After Intravenous and Oral Administration.- I. Proscillaridin A.- II. Meproscillarin.- C. Metabolism and Excretion Pathways.- I. Proscillaridin A.- II. Meproscillarin.- D. Elimination Rate.- I. Proscillaridin A.- II. Meproscillarin.- References.- Pharmacokinetics - Additional Pharmacokinetic Parameters of Cardiac Glycosides.- 5 Plasma Protein Binding of Cardiac Glycosides.- A. Introduction.- B. Characterization of Plasma Protein Binding.- C. Role of Albumin Binding in Pharmacokinetics.- D. Conclusion.- References.- 6 Intestinal Absorption and Secretion of Cardiac Glycosides.- A. Introduction.- B. Intestinal Absorption of Cardiac Glycosides.- I. Dependence on Polarity.- 1. Results Compatible with Diffusion.- a) Natural Glycosides.- b) Semisynthetic Glycosides.- 2. Results Incompatible with Diffusion.- II. Dependence on Dose.- 1. Results Compatible with Diffusion.- 2. Results Incompatible with Diffusion.- III. Dependence on Inhibitors.- 1. Results Compatible with Diffusion.- 2. Results Incompatible with Diffusion.- IV. Dependence on Time.- 1. Results Compatible with Diffusion.- 2. Results Incompatible with Diffusion.- V. Dependence on Blood Flow and Lymph Drainage.- C. Intestinal Secretion of Cardiac Glycosides.- I. Secretion by the Isolated Mucosa of Guinea Pig Jejunum.- II. Secretion by the Isolated Mucosa of Guinea Pig Ileum and Colon.- III. Secretion by the Isolated Mucosa of Human Intestine.- IV. Intestinal Secretion of Glycosides in Vivo.- V. Comparative Aspects of Intestinal Glycoside Secretion.- D. A Concept for the Intestinal Permeation of Cardiac Glycosides.- E. Conclusions.- References.- 7 Cardiac Uptake and Binding of Cardiac Glycosides.- A. Introduction.- B. Experimental Approaches.- C. Uptake of Radiolabeled Cardiac Glycosides by Superperfused Cardiac Preparations.- I. General Characteristics and Kinetic Properties.- II. Characteristics of Uptake in Relation to Rate of Stimulation.- D. Uptake of Cardiac Glycosides by Perfused Cardiac Preparations.- I. Gross Cardiac Uptake of Cardiac Glycosides in Relation to their Effects.- II. Kinetic Properties of Cardiac Glycoside Extraction by Cardiac Preparations.- III. Translocation of Cardiac Glycosides from their Initial Site of Interaction.- IV. Characteristics of Microsomal Cardiac Glycoside-Binding Sites.- 1. Microsomal Content in Relation to Pharmacologic Effect.- 2. General Kinetic Considerations.- 3. Species Differences.- 4. Agents that Reduce the Microsomal Content of Cardiac Glycosides.- E. Binding of Cardiac Glycosides to Fragmented Cardiac Membranes.- F. Summary.- References.- 8 Bioavailability of Cardiac Glycosides.- A. General Aspects.- B. Methods of Measurement.- C. Digoxin Tablets.- D. Other Digoxin Formulations.- E. Other Cardiac Glycosides.- I. Digitoxin.- II. Lanatoside C.- III. Methyldigoxin and Acetyldigoxin.- F. Effect of Nonbiopharmaceutical Factors.- I. Impairment by Drug Interaction.- 1. Neomycin.- 2. Sulphasalazine.- 3. Diphenylhydantoin.- 4. p-Amino salicylic Acid.- 5. Antacids.- 6. Anion-Exchange Resins.- 7. Activated Charcoal.- II. Gastrointestinal Disease.- G. Conclusions.- References.- 9 Pharmaceutical Quality Control Standards for Cardiac Glycosides.- A. Introduction.- B. Cardiac Glycoside Preparations in Clinical Use.- C. Quality Control Standards and Test Procedures.- I. Bulk Drug.- 1. Description and Solubility.- 2. Identity Tests.- 3. Specific Optical Rotation.- 4. Assay Methods.- a) Biologic.- b) Chemical Assays.- c) Presence of Foreign Substances.- d) Loss on Drying.- e) Ash.- f) Microbial Tests.- II. Pharmaceutical Preparations.- 1. Injections.- 2. Elixirs/Tinctures/Solutions.- a) Elixirs.- b) Tinctures.- c) Solutions.- 3. Tablets and Capsules.- a) Tests for Identity and Assay.- b) Physicochemical Test Requirements for Solid Dosage Products.- III. General Pharmacopeial Tests Applied for Formulated Products.- IV. Product Stability.- V. The Future.- References.- Clinical Pharmacology.- 10 Effects of Cardiac Glycosides on the Failing and Nonfailing Heart.- A. Introduction.- B. Fundamental Positive Inotropic Action.- I. Failing Ventricle.- II. Normal Ventricle.- III. Diseased Nonfailing Ventricle.- IV. Atrial Myocardium.- C. Cardiac Energetics.- I. Normal Ventri…