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  • 4‴-Methyldigoxin  (1)
  • O-demethylation  (1)
  • Tritiated metabolites  (1)
  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of spironolactone in man (1976)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 296 (1976), S. 37-45 
    Details
    ISSN: 1432-1912
    Keywords: Spironolactone ; Pharmacokinetics ; Metabolic pathways ; Urinary and fecal excretion ; Fluorigenic metabolites ; Tritiated metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Five healthy male volunteers received 500 mg Aldactone® orally together with 100 μCi 3H-20-21-spironolactone; one elderly patient received 1 mCi 3H-spironolactone without additional ‘cold’ drug. For 6 days the disposition kinetics of the drug were studied in plasma, urine and feces. The tritium concentrations in plasma reached a peak between 25–40 min after administration amounting to 2–3% of the dose/1. Up to the 12th h, they fell rapidly and showed a monoexponential decline (t 1/2 : 2.57±0.27 days) between the 36th and 96th h. Later, a striking increase in the speed of elimination of radioactivity from plasma (t 1/2 : 1.66±0.21 days) was observed. The biological half-life of labeled material in plasma was longer than that of fluorigenic compounds. 47–57% of the dose were excreted in urine and the remaining amount culd be detected in feces (total recovery 90%). The half-life of the urinary excretion rate was distinctly shorter (t 1/2 : 0.9±0.11 days) than that of total radioactivity in plasma. This, together with an observed increase of the polar fraction in urine from 35 up to 85%, which was accompanied by a decrease in plasma from 55 to 35%, suggests either tubular reabsorption or enterohepatic recirculation of lipophilic compounds. TLC-separation of the lipophilic fraction in urine revealed two previously unknown compounds of which the main congener was identified as 3-(3-oxo-7α-methylsulfonyl-6β, 17β-dihydroxy-4-androsten-17α-yl) propionic acid γ-lactone, as well as canrenone and the metabolites which have already been described (Karim and Brown, 1972; Karim et al., 1975). This metabolite represents the main lipophilic degradation product in urine within the first hours, whereas the 6β-OH-7α-methylsulfinylspirolactone leveled off and seemed to be an endexcretion product. For further characterisation, the polar fraction was subjected to acidic hydrolysis. The known metabolic pathways of spironolactone degradation are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00498838
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Disposition of β-methyldigoxin in man (1975)
    Springer
    European journal of clinical pharmacology 9 (1975), S. 105-114 
    Details
    ISSN: 1432-1041
    Keywords: Methyldigoxin ; excretion ; deep compartment ; O-demethylation ; glycosides ; metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time course of radioactivity in plasma and the excretion in urine and faeces over 7 days were determined in 12 healthy subjects after single oral and intravenous doses of a solution of3H-β-methyldigoxin. 62.2±2.1 and 29.0±5.2 per cent of the dose were excreted in urine and faeces, respectively, within 7 days of intravenous administration, compared with 55.2±2.8 and 28.6±5.7 per cent after oral administration. This indicates almost complete absorption of the glycoside when given in solution. 12 hours after its administration a pseudo-distribution equilibrium was reached and the average half life of tritiated compounds was 1.3 days. By 48 – 96 hours after treatment the average half life was 2.8 days. O-demethylation was revealed as the main metabolic degradation step in man. The rate of Demethylation was higher after oral than i.v. administration. Thus, only 31% of the radioactivity excreted in the urine consisted of unchanged β-methyldigoxin after oral administration compared to 51% after i.v. dosing. Only traces of bis- and monoglycosides were excreted in urine, but there were considerable amounts in faeces, where they accounted for more than 35% of the total excretion. Up to 40% of the radioactivity in plasma and urine consisted of polar conjugates during the first 12 hours after administration of β-methyldigoxin. The mono- and bisglycosides were identified as the main products of conjugation. During the 7 days approximately 15% of the administered dose was metabolized by splitting off glycosidic bonds and conjugation to polar compounds.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00614005
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Effects of pretreatment with spironolactone on pharmacokinetics of 4‴-methyldigoxin in man (1976)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 292 (1976), S. 87-92 
    Details
    ISSN: 1432-1912
    Keywords: Spironolactone ; 4‴-Methyldigoxin ; Half life in plasma ; Biliary, faecal and renal excretion ; Metabolism ; Clinical pharmacology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Pharmacokinetics of 3H-4‴-methyldigoxin (md) were studied in three paired experiments with and without pretreatment with spironolactone (7 mg/kg/day for 7 days) and in one additional test person after pretreatment only. The results were compared with controls after oral (n=6) and intravenous (n=6) administration of md. In addition the biliary excretion of md and its metabolites was investigated in biliary fistula patients with and without pretreatment with spironolactone. After pretreatment of normal persons maximum plasma levels of tritium were approximately 35% lower and they were reached on average 60 min after oral administration as compared with approximately 15 min without pretreatment. Already 12 hrs after oral administration the plasma concentrations, with and without pretreatment, no longer differed and the biological half lives of radioactivity in plasma were equal. With or without pretreatment, the cumulative excretion of tritium in urine and faeces was nearly identical in the paired experiments within 7 days. It was in the range of the controls which eliminated 55.2±2.8 and 28.6±5.7% of the dose in urine and faeces, respectively, after oral, and 62.2±2.1 and 28.9±5.2%, respectively, after i.v. administration. Accordingly after pretreatment the radioactivity excreted in bile within 48 hrs (14.9% of the dose) did not differ from controls. Examination of the composition of labelled compounds excreted in urine and bile revealed no significant alterations in the metabolic degradation of md under the influence of spironolactone. Thus the profound effects of spironolactone upon pharmacokinetics of md previously observed in rats are without any significance for human conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00506494
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    Paper (German National Licenses)
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