Pharmacokinetics of Fluvastatin After Single and Multiple Doses in Normal Volunteers

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 3 H 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 bioavailability 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 3 Hfluvastatin 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 reversibiy 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 3 Hfluvastatin described in the present report was safe and well tolerated.