Metabolism and excretion of digitoxin in man

Abstract

The levels of digitoxin and its metabolites in the plasma, urine, and feces of 6 subjects given a single oral dose of 1 mg 3H-dgt have been determined using CHCl3-extraction and thin-layer chromatography (TLC). The peak plasma level of 4.1 % of the given dose per 1 plasma occurred at 40 min after drug administration and was followed by an exponential decline with a mean half-life (T /2) of 6.8 days. The T /2 of the eliminated radioactivity in urine and feces was 7.2 and 4.8 days, respectively. Within 192 hr, 22% of the given dose has been excreted in urine and 13% in feces. The TLC separation of the CHCl,-soluble fraction in plasma yielded the unchanged digitoxin (dgt) and traces of digitoxigenin-bisdigitoxoside (dgt-bis). In urine, dgt accounted for 60% of the eliminated amount within the experimental time. Dgt-bis and the hydroxylated products digoxin (dg) and dgt-bis were also found in lesser anwunts. The monodigitoxoside of digitoxigenin (dgt-mono) could be denwnstrated as a conjugative partner of glucuronic acid. In feces, the unchanged dgt and its monoderivative were the main excretion products. However, since dgt-mono and the more polar compounds have shown an inverse relationship during the study, a bacterial cleavage following a conjugation of dgt-nwno and an enterohepatic circulation of its lipophilic nwiety are suggested. These results demonstrate the limited degradation of dgt in man and suggest that the pharmacologic effects are mediated by dgt itself.The high metabolite-to-digitoxin ratio in the liver of patients receiving 14C_dgt suggests that the liver plays an important role in the elimination of dgt in man. 16 One of the factors that regulates the plasma concentration of dgt seems to be the rate at which the glycOSide is metabolized in the liver. Dgt is excreted more slowly than dg, so that the half-life time (T/2) for dgt is approximately 6 days,7 whereas the T /2 for dg after oral administration is calculated between 31 and 41 hours. 4 ,6 This striking difference among the two glycosides suggests that the ,a-hydroxylation of dgt at C-12 plays a minor role in the metabolic degradation and excretion of this glYCOSide. In man, dgt may be converted into another or into several metabolites, which may have the same elimination rates as the parent substance. The purpose of this study is to elucidate the routes of metabolism of dgt and the rate of its degradation in man.

Effect of Plastic Deformation on the Proof Strength and Electrical Conductivity of Copper-Magnesium Supersaturated Solid-Solution Alloys

“…7) In various SS copper alloys including Cu-Zn, Cu-Al, and Cu-Sn, ¾ L in eq. (2) is more dependent on «¾ b « than «¾ G «, and thus ¾ L and the effect of SS hardening (· ¹ · 0 ) increase with increasing 17) This is in conformity with the result that PS at ¾ = 0 increases with increasing LSF. The Fig.…”

The onset of twinning in metals: a constitutive description

“…The strong decrease in the twinning stress, observed when Mo is alloyed with Rh, has also been attributed to a SFE decrease [62]. Figure 3 shows a compilation of results by Venables [40] and Vöhringer [68]. The twinning stress for a number of copper alloys is shown to vary with the square root of the SFE.…”

Disposition of digitoxin in renal failure

“…The disposition of digitoxin in healthy humans has been characterized by a slow rate of 20 Our data on the elimination kinetics of digitoxin in 6 uremic patients whose clearance of creatinine was almost totally abolished (on average 96%) show that after an oral dose of I mg 3H-dgt the mean concentrations of total radioactivity in plasma do not differ significantly from those in normal subjects. The renal elimination of tritiated compounds was reduced to about 60% of that in controls, whereas the average fecal excretion of dgt and its metabolites was not significantly increased.…”

“…20 An improved procedure of the tritium extraction from the body fluids lead to a mean recovery in plasma of 90.1 ± 0.87%, in urine of 95.0 ± 0.6%, and in feces of 9l.0 ± 0.8%, respectively, from the primary radioactivity count. These results were obtained in comparison to those previously reported,20 from lyophilized plasma samples extracted 4 times with 10 ml dichlormethan/methanol 1: 1 (instead of 3 times).…”