Metabolic Fate of Fluvastatin, an Inhibitor of HMG-CoA Reductase (1): Absorption, Distribution and Excretion of [¹⁴C]Fluvastatin after Single Administration in Rats

Abstract

Fluvastatin (FV) is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Absorption, distribution and excretion of the drug were investigated in rats after single administration of [¹⁴C]FV.
1. After oral administration of [¹⁴C]FV at doses of 0.25, 1, 5, 10 and 20 mg/ kg, the radioactivity in the blood reached the maximum concentration (C_max) between 1 and 2 hr, and declined with half-lives range of 7 ?? 11 hr. The values of both C_max and AUC increased in a dose-dependent manner. [¹⁴C]FV was absorbed mainly from the intestine, and the extent of absorption was estimated to be 61 ?? 84%.
2. Concentration of the unchanged FV in the plasma reached the maximum at 0.5 hr after oral administration of [¹⁴C]FV, and decreased with half-life of 3 ?? 4 hr. Bioavailability of the drug was about 46% at 1 mg/kg.
3. Distribution of the radioactivity to tissues was rapid and the maximum concentrations were attained within 2 hr after oral administration (1 mg/kg). Majority of the radioactivity was found in the liver and gastro-intestinal contents. At 24 hr, the levels of the radioactivity in the liver and intestinal contents were low, and those in another tissues were negligible.
4. Plasma protein binding of [¹⁴C]FV was over 97 ?? 99% in rat, dog and human. Binding ratio of [¹⁴C]FV to human serum albumin showed to be 94 ?? 97%. After oral administration of [¹⁴C]FV to rats, binding ratio of the radioactivity to plasma protein was 97 ?? 99%.
5. Excretion of the radioactivity in urine and feces within 144 hr after oral dosing was 4% and 95% of the dose, respectively. In bile duct-cannulated rat, biliary excretion was 83%, and the 58% of the radioactivity excreted into bile was reabsorbed.
6. No sex difference was observed in the pharmacokinetic parameters.