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NK-104 is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase with a very potent lipid-lowering effect. Biotransformation profiles of NK-104 in bile from rat, rabbit and dog given an intravenous infusion of NK-104 were investigated. Structural assignment was made by liquid chromatography (LC)-mass spectrometry (MS)-MS and proton NMR analyses. The predominant component was intact NK-104 in all the animals. At least eight other metabolites were present in rat, four in rabbit, and 10 in dog. These bile metabolites were purified and isolated by preparative HPLC. Biotransformation pathways elucidated for NK-104 were as follows: (a) lactonization ; (b) beta-oxidation of the side-chain; (c) hydroxylation of the quinoline ring; (d) conjugation with Beta-glucuronic acid and taurine. Beta-oxidative degradation of the side-chain in the case of other HMG-CoA reductase inhibitors is necessary for epimerization of the hydroxy group which has an R-configuration. However, M-16, glucuronide of the ketolactone derivative, was obtained as a key metabolite suggesting another beta-oxidation pathway for the side-chain.

Identification of Metabolites of NK-104, an HMG-CoA Reductase Inhibitor, in Rat, Rabbit and Dog Bile.