TOLRESTAT PHARMACOKINETICS IN RAT PERIPHERAL-NERVE

The clinical efficacy of an aldose reductase (AR) inhibitor in diabeti c polyneuropathy depends on its bioavailability at the site(s) of AR i n peripheral nerves. Accordingly, the link between the concentration o f the AR inhibitor, tolrestat, and the extent of its inhibition of the AR-catalyzed polyol production was investigated in sciatic nerves of galactosemic rats. Tolrestat was administered by gavage (1 x 150 mg/kg , or 5, and 15 mg/kg/day for 15 days to attain steady state as estimat ed from the 53-h half-life of tolrestat determined in rat nerve); subs equently, at six time intervals, ranging from 4 to 59 days, rats were given access for 4 days to a 20% galactose diet, and killed. At every time point, the composite tolrestat concentration in the nerve correla ted with the percentage decrease in nerve galactitol (r = 0.857, p = 0 .0015). Because the latter should reflect the extent of nerve AR inhib ition by tolrestat, the concentration of ''free'' tolrestat available at the site(s) of AR in the nerve was estimated from the tolrestat con centration/percent AR inhibition plot obtained in vitro. The estimated amount of tolrestat present at the site(s) of nerve AR represented 0. 4% of the composite tolrestat concentration measured in the nerve. The results support the view that the effectiveness of an AR inhibitor in peripheral nerve depends on its pharmacokinetics in the nerve, i.e., on its uptake, nonspecific binding to cellular constiuents, and elimin ation.