Pharmacokinetics of the Aldose Reductase Inhibitor, Zopolrestat, in Humans

The pharmacokinetics of zopolrestat, an aldose reductase inhibitor that may be useful for the treatment of complications of diabetes, have been investigated using oral doses ranging from 50 to 1200 mg administered to healthy male volunteers. In a single-dose study, Cmax, AUC(0–48), and urinary elimination of zopolrestat increased linearly with increasing dose. The amount of zopolrestat excreted unchanged in the urine within 48 hours ranged from 34 to 45% of the administered dose. Renal clearance ranged from 2.6 to 5.6 mL/min, and appeared to decrease as the dose was increased. In a 2-week multiple dose study, the mean steady-state minimum and maximum plasma concentrations, Cmin and Cmax, were 91.5 and 196 μg/mL for subjects administered 800 mg/day, and 131 and 281 μg/mL for subjects administered 1200 mg/day. Steady-state AUC(0–24) was also dose proportional. The mean steady state half life of about 30.3 hours was consistent with the observed 2.2-fold accumulation in plasma. Apparent oral clearance (Clpo) was 5.2 mL/min, and apparent volume of distribution (Vdss/F) was 12 L. Mean renal clearance was 2.2 mL/min, and approximately 45% of the administered dose was excreted into the urine at steady state. There was no effect of food consumption during dosing on the extent of absorption of zopolrestat. In in vitro studies, extensive, concentration-dependent binding of zopolrestat to plasma proteins was observed. These data indicate that once-daily dosing of zopolrestat will provide suitable exposure in the treatment of diabetic complications.