Abstract

The metabolic pathways of fluvastatin sodium (FV; Lescol, Sandoz compound XU 62-320), [R*,S*-(E)]-(+-)-sodium-3,5-dihydroxy-7-[3- (4-fluorophenyl)-1-(1-methylethyl)-1H-indole-2-yl]-hept-6-enoate, a potent inhibitor of hydroxy-methylglutaryl-CoA reductase (HMG-CoA reductase)--the rate-limiting enzyme in cholesterol biosynthesis--were determined in normal male volunteers at steady state. The metabolite profiles were determined in pooled human blood/plasma, urine, and feces obtained from healthy male volunteers after a single dose of 2 and 10 mg of [3H]FV and at steady state after a single 40 mg daily dose of [3H]FV for 6 sequential days utilizing HPLC coupled with radioactivity monitoring. The two major components in plasma were FV and the desisopropylpropionic acid (4) derivative of FV, the latter a result of oxidative removal of the N-isopropyl group and beta-oxidation of the side chain. Minor amounts of the 4,5-pentenoic acid derivative of FV, the threo-isomer of FV, the trans-lactone of FV, and conjugates of 5-hydroxy FV and 6-hydroxy FV were also present in plasma. Parent FV was not present in feces, the major excretory route, or in urine. In urine, 4 and conjugates of 5-hydroxy FV, and 6-hydroxy FV were present, and each represented < 1% of the dose. In feces 5-hydroxy FV, 6-hydroxy FV, and desisopropyl-FV represented the only peaks of significance. The metabolism of FV leading to the 5-hydroxy FV and 6-hydroxy FV was not stereospecific.(ABSTRACT TRUNCATED AT 250 WORDS)