Studies on the Metabolic Fate of NK-104, a New Inhibitor of HMG-CoA Reductase (1) : Absorption, Distribution, Metabolism and Excretion in Rats

Abstract

NK-104 is a synthetic inhibitor of 3 hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase with very potent lipid-lowering effect. Absorption, distribution, metabolism and excretion of NK-104 were investigated after a single oral or intravenous administration of 14C-NK-104 at a dose of 1 mg/kg to rats, mainly males. 1. The total radioactivity in plasma reached maximum levels within 1 hr after oral administration to male and female rats, and was followed by the elimination process consinting of three exponential. The T1/2 in the terminal phase was relatively long (12 ?? 18 hr). Although the Cmax was 325 and 415 ng eq./ml in males and females, respectively, the AUC was similar indicating no sex-related difference. 2. The tissue distribution was examined by both whole body autoradiography and quantitative radioassay. Following oral administration to rats, the radioactivity was selectively distributed to the liver, a target organ of this drug. The Cmax was approximately 54 times higher in the liver than in plasma. 3. Almost all the radioactivity was excreted into feces after oral or intravenous administration to male and female rats, respectively. Biliary excretion was 75% up to 48 hr after oral administration and most of the drug was subjected to entero-hepatic circulation. 4. After oral administration to rats, the unchanged NK-104 was detected as the main component and a small amount of several metabolites was also detected in plasma and various tissues. In particular, the Cmax and AUC of NK-104 in the liver were approximately 20 and 30 times, respectively, higher than those in plasma. In the present study, it is concluded that NK-104 is hardly metabolized via P-450 mediated oxidation resulting in the formation of few products of β-oxidation.