The pharmacokinetics of fluvastatin, a potent inhibitor of hydroxymethylglutaryl-CoA reductase and thus cholesterol synthesis, have been studied in 24 normal male volunteers who received [H-3] fluvastatin in three different studies: a single-dose study using oral doses of 2 or 10 mg, an absolute bioavailability study using doses of 2 mg intravenously or 10 mg orally, and a multiple-dose study using 40 mg orally once daily for 6 days. Serial blood and plasma samples and complete urine and feces were collected and analyzed for total radioactivity as well as for intact fluvastatin. Fluvastatin was rapidly and almost completely (>90%) absorbed from the gastrointestinal tract, although the estimated bio-availability from the 2- and 10-mg doses was only 19 to 29% because of extensive first-pass metabolism. Fluvastatin pharmacokinetics appeared to be linear over the 2- to 10-mg dose range, as indicated by dose-proportional blood levels of total radioactivity and the parent drug. Absorbed fluvastatin was completely metabolized before excretion, the biliary/fecal route being the major excretory pathway. The recovery of radioactivity after a single dose was virtually complete within 120 hours. The terminal half-lives of fluvastatin and total radioactivity averaged 0.5 to 1 hour and 55 to 71 hours, respectively, whereas the total body clearance of fluvastatin was 0.97 L/hour/kg. Repeated oral administration of 40-mg doses of [H-3]fluvastatin resulted in no time-related change in pharmacokinetic characteristics, but this dose yielded greater than proportional increases in circulating levels of the parent drug, thus suggesting a saturable first-pass effect on fluvastatin. During repeated daily administration, plasma levels of fluvastatin reached steady state after the first dose, whereas those of total radioactivity approached steady state after 6 days. The degree of accumulation of radioactivity, unlike that of the parent drug, was inconsistent with the terminal half-life, but instead implied a shorter effective half-life of 32 to 36 hours. It appears that the terminal phase of the blood radioactivity profile represents a minor metabolite that is reversibly bound to and slowly released from a specific tissue depot, and that this binding involves a finite amount of drug regardless of the dose administered. The oral and intravenous administration of [H-3]fluvastatin described in the present report was safe and well tolerated.
