Zopolrestat is an
aldose reductase inhibitor that may be useful in the treatment of
diabetic complications by reducing flux through the
polyol pathway. The plasma half-life of
zopolrestat in man is approximately 30 h, and approximately 45% of an orally administered 1000-mg dose is eliminated in the urine as unchanged
drug. Because active secretion accounts for much of the renal clearance for
zopolrestat, a
carboxylic acid with a pK(a) of 5.46, the effect of urinary pH and flow rate on renal clearance of
drug was investigated in a series of studies. Renal clearance of
zopolrestat following
oral administration of 200 mg was determined in normal male volunteers under basal conditions and
after treatment with NH(4)Cl and NaHCO(3) to alter urinary pH. Plasma concentrations of
zopolrestat were similar under basal and NaHCO(3) treatment but were approximately twofold higher under NH(4)Cl treatment. However, the half-life of
zopolrestat under NH(4)Cl treatment (29.5 h) was similar to the half-life of
zopolrestat in untreated subjects. Renal clearance decreased by
a factor of 2.54 for each unit decrease in urinary pH. In a second study, there was no effect of urine flow rate on renal clearance following an oral dose of 400 mg. Renal elimination of
zopolrestat and
zopolrestat glucuronide was also examined in volunteers with normal urine flow dosed at either 600 or 1000 mg/day. Whereas renal clearance of
zopolrestat decreased with decreasing urinary pH, renal elimination of
zopolrestat glucuronide was not affected by pH.