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Research ArticleArticle

14C-Propoxyphene Demethylation in the Rat

An example of differences between liver and intestinal drug-presystemic metabolism

Yves Horsmans, Alain Saliez, Véronique Van Den Berge, Jean-Pierre Desager, André P. Geubel, Stanislas Pauwels and Luc Lambotte
Drug Metabolism and Disposition November 1997, 25 (11) 1257-1259;
Yves Horsmans
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Alain Saliez
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Véronique Van Den Berge
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Jean-Pierre Desager
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André P. Geubel
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Stanislas Pauwels
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Luc Lambotte
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An example of differences between liver and intestinal drug-presystemic metabolism

Abstract

Presystemic metabolism is believed to occur mainly in the liver with some minor intestinal participation. The aim of this study was to investigate the respective part of each of these two organs in the metabolism of the analgesic d-propoxyphene (DP). Pharmacological doses of DP were given in the duodenum (ID), the portal vein (IP), and the femoral vein (IV) of male Wistar rats. A tracer dose of14C-DP was also administered either in IV, IP, or ID as well as in hepatectomized rats or rats with bile duct diversion.In vitro demethylation occurring in liver and intestinal microsomes was also studied. Absolute DP bioavailability obtained after oral administration was two times higher than that observed after portal administration (48.9% vs. 23.2%, respectively), an result opposite (i.e. a lower bioavailability) of that expected on the basis of the existence of a liver enzyme saturation phenomenon. The 14CO2 cumulative excretion after 14C-DP administration was significantly lower after IV or ID administration than after injection in the portal vein as a bolus or within 20 min. The biliary excretion of the labeled compound varied in the opposite direction, being greater after IV or ID than after IP administration, suggesting that the metabolism of DP in the liver is influenced by an extrahepatic transformation. This most likely occurs in the gut since the production of 14CO2after IV administration was similar to that after ID administration. This transformation did not prohibit DP detection in the systemic blood but was sufficient to increase the part eliminated with bile and to decrease the part demethylated into NP. Demethylation mainly occurs in the liver since the production of 14CO2 was nearly abolished in hepatectomized rats. Furthermore, microsomes of hepatic but not of intestinal origin were able to demethylate DP. Our data suggest that the transformation of DP occurring in gut after oral administration is responsible for changes in the hepatic metabolism of the drug.

Footnotes

  • Send reprint requests to: Y. Horsmans, M.D., Ph.D., Department of Gastroenterology, Cliniques Universitaires Saint Luc, Avenue Hippocrate, 10, 1200 Brussels, Belgium.

  • Abbreviations used are::
    DP
    d-propoxyphene
    ID
    intraduodenal
    IP
    intraportal
    NP
    norpropoxyphene
    • Received August 6, 1996.
    • Accepted July 15, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 25, Issue 11
1 Nov 1997
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Research ArticleArticle

14C-Propoxyphene Demethylation in the Rat

Yves Horsmans, Alain Saliez, Véronique Van Den Berge, Jean-Pierre Desager, André P. Geubel, Stanislas Pauwels and Luc Lambotte
Drug Metabolism and Disposition November 1, 1997, 25 (11) 1257-1259;

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Research ArticleArticle

14C-Propoxyphene Demethylation in the Rat

Yves Horsmans, Alain Saliez, Véronique Van Den Berge, Jean-Pierre Desager, André P. Geubel, Stanislas Pauwels and Luc Lambotte
Drug Metabolism and Disposition November 1, 1997, 25 (11) 1257-1259;
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