Studies on the Disposition of Finasteride. (V): Metabolic Disposition of Finasteride and Identification of Metabolites Reabsorbed into the Entero-Hepatic Circulation in Rats.

  • ISHII Yasuyuki
    Pharmacokinetics, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd
  • TANI Takeshi
    Drug Metabolism, Development Research Laboratories, Banyu Pharmaceutical Co., Ltd
  • ISHII Mikio
    Drug Metabolism, Development Research Laboratories, Banyu Pharmaceutical Co., Ltd
  • ISHIZAKI Hiroyuki
    Drug Metabolism, Development Research Laboratories, Banyu Pharmaceutical Co., Ltd
  • KAMEI Toshio
    Drug Metabolism, Development Research Laboratories, Banyu Pharmaceutical Co., Ltd
  • NAGAI Tsuneji
    Department of Pharmaceutics, Hoshi University

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The concentrations of finasteride, an inhibitor of steroid 5α-reductase, and its metabolites in plasma, urine, bile, and tissue was assayed after oral or intravenous administration of 14C-finasteride to rats using radio-HPLC.<BR> Finasteride accounted for approximately 50% of plasma radioactivity after oral or intravenous administration of 14C-finasteride to male rats. The major metabolites of finasteride, side-chain hydroxylated (M-1) and 6 α-OH (M-4) finasteride, accounted for 12%-27% of plasma radioactivity. Almost all of the orally administered 14C-finasteride was excreted into bile and the metabolites accounted for most of the biliary radioactivity. This shows that metabolism was the major route of drug elimination in rats. The side-chain oxidation and ring hydroxylation were the major pathways. At 0.5 hr after oral dosing, approximately 60% of the radioactivity in the liver was attributable to metabolites, and the intact drug accounted for almost half of the radioactivity present in the kidney, suggesting rapid distribution of finasteride.<BR> To identify the metabolites reabsorbed during the entero-hepatic circulation, the small intestine contents, small intestine, portal vein and abdominal aorta plasma, liver, and bile of the rats were assayed for metabolites after intraduodenal injection of the bile samples obtained from other rats orally administered with 14C-inasteride. Finasteride ω-acetic acid (M-3) was mainly found and was present in all samples except in portal vein plasma. This metabolite as well as ω, 6α-(OH)2 finasteride (M-5), which was formed in the small intestine during absorption, were converted to glucuronides in the small intestine tissue and then influxed into the portal vein blood. In the liver, these conjugates were hydrolyzed to their aglycones, some of which were further oxidized. The metabolite composition of the bile was comparable to that of the administered bile.<BR> These findings suggest that almost all of the orally administered 14C-finasteride was metabolized in the liver. The metabolites were excreted into the bile and then reabsorbed into the entero-hepatic circulation. The metabolites M-3 and M-5 were mainly reabsorbed into the entero-hepatic circulation, undergoing glucuronidation in the small intestine and hydrolysis and oxidation in the liver.

収録刊行物

  • 薬物動態

    薬物動態 13 (1), 36-44, 1998

    日本薬物動態学会

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