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Effect of enterohepatic circulation on the pharmacokinetics of spironolactone in man

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Summary

100 μCi 3H-spironolactone together with 300 mg unlabeled drug were administered orally to 8 patients, 24 h after choledochotomy with subsequent complete drainage of bile for a further 96 h by means of a special tube. To evaluate the role of entero-hepatic circulation, the excretion of tritiated substances in bile was investigated and their kinetics in plasma and urine were compared with that of controls.

The 3H-activity in plasma declined monoexponentially with t 1/2: 1.80±0.12 d from 12 h after patients received the drug. This half life was not different from that of controls in the terminal slope, 96–144 h after administration. However, between 24–96 h the elimination was significantly delayed (t 1/2: 2.79±0.29 d) in controls. This was the result of entero-hepatic cycling of spironolactone metabolites with high biliary clearance.

5.4–32.7% of the dose was excreted in bile within 4 days; of this 50–70% consisted of polar material, 10–20% of canrenone, 5–15% of 6β-OH-7α-methylsulfinyl-spirolactone and 3–10% of 6β-OH-7α-thiomethyl-spirolactone. In urine, identical percentages of the dose were excreted in patients and controls. TLC-examination of the lipophilic fraction revealed less sulfoxidized metabolites while, at the same time, significantly higher amounts of 6β-OH-7α-thiomethylspirolactone and canrenone were eliminated in patients with biliary fistula.

Thus, interruption of enterohepatic circulation had resulted in a shift of metabolic pathways of this drug in spite of an unchanged overall metabolic rate. Furthermore, the experiments allow a logical interpretation of the kinetics of 3H-activity in plasma after administration of 3H-spironolactone in normal man.

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Authors and Affiliations

  1. Institut für Klinische Pharmakologie und Medizinische Klinik, Klinikum Steglitz, Freie Universität Berlin, Hindenburgdamm 30, D-1000, Berlin 45

    U. Abshagen, U. von Grodzicki, U. Hirschberger & H. Rennekamp

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  1. U. Abshagen
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  2. U. von Grodzicki
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  3. U. Hirschberger
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  4. H. Rennekamp
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This paper includes parts of the thesis of U. Hirschberger

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Abshagen, U., von Grodzicki, U., Hirschberger, U. et al. Effect of enterohepatic circulation on the pharmacokinetics of spironolactone in man. Naunyn-Schmiedeberg's Arch. Pharmacol. 300, 281–287 (1977). https://doi.org/10.1007/BF00500971

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  • DOI: https://doi.org/10.1007/BF00500971

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