TOLRESTAT PHARMACOKINETIC AND PHARMACODYNAMIC EFFECTS ON RED-BLOOD-CELL SORBITOL LEVELS IN NORMAL VOLUNTEERS AND IN PATIENTS WITH INSULIN-DEPENDENT DIABETES

Objectives: To examine the effect of diabetes mellitus on the pharmaco kinetics of tolrestat and to investigate its effect on red blood cell sorbitol levels according to a new pharmacodynamic model for this clas s of drugs. Methods: Single and multiple doses of tolrestat (200 mg/tw ice a day) were administered to 12 patients with insulin-dependent (ty pe I) diabetes and 12 healthy volunteers in an open parallel trial. Re sults: Tolrestat disposition was characterized by first-order absorpti on and biexponential disposition: In normal subjects the terminal disp osition half-life (t(1/2)) was 13 +/- 3 hours (mean +/- SD) and the ap parent oral clearance (CL/F) was 48 +/- 9 ml/hr/kg, similar to the val ues in patients with type I diabetes mellitus (t(1/2) = 14 +/- 4 hours ; CL/F = 55 +/- 10 ml/hr/kg), Red blood cell sorbitol concentrations, which declined because of tolrestat's inhibition of aldose reductase, were characterized by an indirect-response model including a 50% inhib ition constant (IC50) for production of sorbitol by aldose reductase, The removal of sorbitol (k(out)) was slower in patients with diabetes, The plasma IC50 averaged 2.0 +/- 1.3 mu g/ml in normal subjects and 2 .5 +/- 1.9 mu g/ml in patients with diabetes. IC50 values expressed in free (unbound) concentrations (f(u) = 0.64%), which ranged from 12 to 16 ng/ml, were similar to the in vitro IC50 for inhibition of sorbito l accumulation in human red blood cells. Conclusions: Tolrestat pharma cokinetics were similar in normal subjects and in patients with diabet es; however, the patients with diabetes had higher baseline sorbitol l evels (11 versus 5 nmol/ml for normal subjects) and slower sorbitol ef flux rates, The proposed biochemically realistic, dynamic model charac terized well the red blood cell sorbitol response patterns after admin istration of single and multiple doses of tolrestat.