Studies on the Metabolic Fate of NK-104, a New Inhibitor of HMG-CoA Reductase. (2). Absorption, Distribution, Metabolism, Excretion and Accumulation Following Repeated Oral Administration of 14C-NK-104 in Rats.

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NK-104 is a very potent competitive inhibitor of HMG-CoA reductase. In this study, the absorption, distribution, excretion and metabolism of 14C NK-104 were investigated during and after repeated oral administration to male rats at a daily dose of 1 mg/kg for nine days. The levels of radioactivity in the plasma at 0.5 and 24 hr after daily dosing reached a steady state after the 4th administration, and levels were about 2 times higher than those after the 1st administration. High levels of radioactivity were detected in the liver during the repeated administration with maximum levels being 35-51 times higher than those in plasma. The level of radioactivity in other tissues after final administration was about 3 times that after the 1st administration. The elimination of radioactivity from the tissues was rapid and complete by 144 hr after the final administration. The excretion ratio of radioactivity in the urine and feces up to 144 hr after the 9th administration was 0.14 and 97.91%, respectively. Unchanged NK-104 was mainly found in plasma during the repeated oral administration. Two major metabolites, M-6 (pentenoic acid derivative) and M-8 (propenoic acid derivative), as β-oxidation products of NK-104, were found in heart and skeletal muscle after the repeated oral administration at levels 2-4 times than after single administration. The radioactivity present in feces predominantly considered of the unchanged drug during the repeated administration. In conclusion, there was no significant accumulation of radioactivity due to repeated administration of 14C-NK-104 to rats.

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  • 薬物動態

    薬物動態 13 (5), 499-507, 1998

    日本薬物動態学会

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