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 pharmacokinetics of tolrestat and to investigate its effect on red blood cell sorbitol levels according to a new pharmacodynamic model for this class of drug. Methods: Single and multiple doses of tolrestat (200 mg/twice a day) were administered to 12 patients with insulin-dependent (type I) diabetes and 12 healthy volunteers in an open parallel trial. Results: Tolrestat disposition was characterized by first-order absorption and biexponential disposition: In normal subjects the terminal disposition half-life (t( 1/2 )) was 13 ± 3 hours (mean ± SD) and the apparent oral clearance (CL/F) was 48 ± 9 ml/hr/kg, similar to the values 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% inhibition 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 μg/ml in normal subjects and 2.5 ± 1.9 μg/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 sorbitol accumulation in human red blood cells. Conclusions: Tolrestat pharmacokinetics were similar in normal subjects and in patients with diabetes; however, the patients with diabetes had higher baseline sorbitol levels (11 versus 5 nmol/ml for normal subjects) and slower sorbitol efflux rates. The proposed biochemically realistic, dynamic model characterized well the red blood cell sorbitol response patterns after administration of single and multiple doses of tolrestat.