Aldose reductase inhibitory and uricosuric activities of FK366 in healthy volunteers.

The pharmacokinetics, and aldose reductase (AR) inhibitory and uricosuric activities of FK366 were studied in healthy volunteers given a single oral dose of 150, 300, or 600 mg after fasting, 600 mg after a meal, or 300 mg twice a day for 8 days after meals. The AR inhibition was assessed by the percent reduction from the predrug dulcitol values in red blood cells converted from exogenous galactose by AR. Aldose reductase inhibition paralleled the plasma concentrations of FK366, with maximum inhibitions of 31.6, 48.0, and 56.9% at doses of 150, 300, and 600 mg, respectively. With multiple dosing, the inhibition scarcely differed between the first (41.8%) and last doses (41.5%). Serum uric acid decreased dose dependently, with a minimum concentration of 4.0 mg/dL (predrug: 5.5 mg/dL) 8 hours after receiving 600 mg. With multiple dosing, serum uric acid levels declined rapidly and remained at a concentration of 3.1 mg/dL beginning at day 3. Urinary excretion of uric acid was high on day 1 (879 mg/day), but decreased significantly to 654 mg/day on day 2 and then stabilized. The pharmacokinetics of FK366 were linear over the dose range studied, with an elimination half-life of 8.2 hours and urinary recovery of 27.2% as unchanged drug. FK366 was well tolerated by all subjects.