Toxicokinetics of zenarestat, an aldose reductase inhibitor in animals and man

Abstract

1. The relationship between dose and plasma concentrations is important in extrapolating toxicity between species. Therefore, we determined this relationship for zenarestat in animals and man.

2. The biopharmaceutics of zenarestat was assessed prior to toxicity testing. The bioavailability of zenarestat in rat administered zenarestat in 0.5% (w/v) methyl cellulose suspension and aqueous solution was similar. Bioavailability in dog administered zenarestat treated with excipients and in aqueous solueion was similar.

3. C_max increases dose-relatedly both in animals and man. AUC increased almost in proportion to the dose in mouse, rat and man, but increased to a greater extent at the highest dose in dog. C_max, AUC and C_24h were not significantly different during/after multiple dosing.

4. After 13 and 53 weeks of toxicity testing, plasma concentrations were not significantly different between the days and sexes except at 560 mg/kg in the female rat and at 56 mg/kg in the female dog in 13 week toxicity tests.

5. The exposure of zenarestat in man, administered 300 mg b.i.d., seemed to be no more than that in animals at non-toxic doses.