M. Kanamaru et al., ALDOSE REDUCTASE INHIBITORY AND URICOSURIC ACTIVITIES OF FK366 IN HEALTHY-VOLUNTEERS, Journal of clinical pharmacology, 33(11), 1993, pp. 1122-1131
The pharmacokinetics, and aldose reductase (AR) inhibitory and uricosu
ric activities of FK366 were studied in healthy volunteers given a sin
gle oral dose of 150, 300, or 600 mg after fasting, 600 mg after a mea
l, 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 redu
ctase inhibition paralleled the plasma concentrations of FK366, with m
aximum inhibitions of 31.6, 48.0, and 56.9% at doses of 150, 300, and
600 mg, respectively. With multiple dosing, the inhibition scarcely di
ffered between the first (41.8%) and last doses (41.5%). Serum uric ac
id 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 conc
entration of 3.1 mg/dL beginning at day 3. Urinary excretion of uric a
cid 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 we
re linear over the dose range studied, with an elimination half-life o
f 8.2 hours and urinary recovery of 27.2% as unchanged drug. FK366 was
well tolerated by all subjects.