PHARMACOKINETICS OF THE ALDOSE REDUCTASE INHIBITOR, ZOPOLRESTAT, IN HUMANS

The pharmacokinetics of zopolrestat, an aldose reductase inhibitor tha t may be useful for the treatment of complications of diabetes, have b een investigated using oral doses ranging from 50 to 1200 mg administe red to healthy male volunteers. In a single-dose study, C-max, AUC(0-4 8), and urinary elimination of zopolrestat increased linearly with inc reasing dose. The amount of zopolrestat excreted unchanged in the urin e within 48 hours ranged from 34 to 45% of the administered dose. Rena l 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 ste ady-state minimum and maximum plasma concentrations, C-min and C-max w ere 91.5 and 196 mu g/mL for subjects administered 800 mg/day, and 131 and 281 mu g/mL for subjects administered 1200 mg/day. Steady-state A UC(0-24) was also dose proportional. The mean steady state half life o f about 30.3 hours was consistent with the observed 2.2-fold accumulat ion in plasma. Apparent oral clearance (Cl-po) was 5.2 mL/min, and app arent volume of distribution (Vd(s5)/F) was 12 L. Mean renal clearance was 2.2 mL/min, and approximately 45% of the administered dose was ex creted into the urine at steady state. There was no effect of food con sumption during dosing on the extent of absorption of zopolrestat. In in vitro studies, extensive, concentration-dependent binding of zopolr estat to plasma proteins was observed. These data indicate that once-d aily dosing of zopolrestat will provide suitable exposure in the treat ment of diabetic complications.