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NK-104 is a very potent competitive inhibitor of HMG-CoA reductase. The pharmacokinetic properties of NK-104 were evaluated after intravenous and/or oral administration to rats, rabbits, dogs, monkeys and humans. The plasma concentration of NK 104 showed triexponential elimination after intravenous administration, with a half-life of 4.0-5.3 h in all four animal species. The absorption was relatively rapid after the oral administration. The relationship between the dose and the AUC was linear at a relatively high dose range in the animal species. In humans, the correlation line was located between those of dogs and rats. High bioavailability (about 80%) at a dose of 1 mg/kg was observed in all animal species except monkeys. These results indicated that the pharmacokinetic properties of NK-104 after oral administration in humans resembled those in dogs, suggesting that the BA of NK-104 is large in humans as well as dogs. NK-104 was excreted mainly into feces via biliary route, and the renal handling was negligible in rats, dogs and humans. On the other hand NK-104 was excreted mainly into urine in rabbits, and was excreted poorly into urine and feces in monkeys. The unchanged drug was excreted mainly in rat bile. Although several β-oxidation products as metabolites of NK-104 were detected, the levels of these metabolites were fairly low. In dogs, the major component in plasma, urine and feces after oral administration was the unchanged NK-104. The β-oxidation products (M-5 and M-8) were also slightly detected only in dogs. In humans, the major components in plasma after repeated oral administration (2 mg/day for 5 days) were NK-104 and its lactone form. These results suggest that NK-104 may be hardly metabolized in humans than in animal species.

Studies on the Metabolic Fate of NK-104, a New Inhibitor of HMG-CoA Reductase. (4). Interspecies Variation in Laboratory Animals and Humans.