Metabolism of cardiac glycosides studied in the isolated perfused guinea‐pig liver

Abstract

Summary1. Metabolic degradation of tritiated ouabain, digoxin, and digitoxin has been investigated quantitatively using the isolated perfused guinea-pig liver. The cardiac glycosides and their metabolites have been extracted from the plasma, liver, and bile by different solvents and identified as far as possible by radiochromatographic analysis.2. The total metabolic activity in the experimental system was localized in the liver.3. The hydrophilic glycoside ouabain could not penetrate into the metabolically active compartment of the liver and was, therefore, not degraded. The more lipophilic compound digitoxin, however, was completely degraded due to its high affinity for the metabolically active sites. The unchanged digitoxin cannot enter the aqueous bile fluid in contrast to its more hydrophilic metabolites. 4. The only detectable metabolic degradation of digoxin was a conjugation with glucuronic and/ or sulphuric acid, but a cleavage of sugar molecules seemed not to occur.5. In the case of digitoxin the metabolic processes are more complicated: sugar cleavage, conjugation, and C-12 hydroxylation take place simultaneously. An immediate hydroxylation of digitoxin leading to digoxin was not observed. After administration of digitoxin conjugation products as well as digoxigeninbis-and digoxigenin-mono-digitoxosides were present in each of the compartments investigated, but the digitoxosides of digitoxigenin were intermediates in concentrations too low to be determined indicating a very high rate of conjugation and/or C-12 hydroxylation as compared with the cleavage of the digitoxoses. 6. A scheme for the metabolic pathways of the cardiac glycosides based on experimental results is presented. The metabolic behaviour of each of the three compounds involved is closely related to their physicochemical properties, especially the lipid solubility.

Molecular interactions with redox sites and salt bridges modulate the anti-aggregatory effect of flavonoid, tannin and cardenolide moieties against amyloid-beta (1–42) in silico

“…This implies a lesser desired effect as gallic acid is metabolized in vivo. The same was done for the cardiac glycosides, with the cardenolide moiety as a representative ligand (Kolenda et al 1971;Rietbrock et al 1977). In contrast, the most favorable binding pose (Fullfitness: − 38,028.785 kcal/mol) of the cardenolide moiety interacted with Aβ 1-42 in the latter part of the first ten residues, particularly with Hsp6 (protonated His) and Tyr10 via hydrophobic interactions (Fig.…”

Histopathological Diagnosis of Suicidal Oleander Poisoning

“…Specially, the lipid-soluble cardiac glycosides are easily metabolized. 6 Also, the laboratory test against this toxin is uncommonly used, leading to negative toxicological analysis report for such cases. Thus, history and evidence surrounding the incident are very important in such cases to draw a conclusion.…”

Plasma concentration, uptake by liver, and biliary excretion of tritiated cardiac glycosides in the isolated perfused guinea‐pig liver

“…9 is further supported by the finding that the T/M ratio of the digitalis glycosides changes throughout the perfusion: in the first 2 h it reaches a value of about 10 and subsequently decreases to approximately 3, thus indicating a continuous increase of the ratio hydrophilic metabolites/lipophilic glycosides in the plasma. The polar metabolites found in the plasma must have been redistributed from the liver into the blood since it has been shown that a conversion of these glycosides does not occur in the blood itself (Kolenda et al, 1971 ;Liullmann et al, 1969). The newly appearing metabolites are distributed between plasma and liver in the same way as ouabain ( Fig.…”

“…The polar metabolites found in the plasma must have been redistributed from the liver into the blood since it has been shown that a conversion of these glycosides does not occur in the blood itself (Kolenda et al, 1971 ;Liullmann et al, 1969). The newly appearing metabolites are distributed between plasma and liver in the same way as ouabain (Fig.…”

“…The non-radioactive metabolites used for reference were made visible by means of colouring with anisaldehyde sulphuric acid reagent (0'5 ml of anisaldehyde in 50 ml of acetic acid plus 1 ml of sulphuric acid: Stahl, 1967). For details see Kolenda, Lullmann & Peters (1971).…”