Dose-Dependent Pharmacokinetics of the Aldose Reductase Inhibitor Imirestat in Man

Autor: Brazzell, R. Kim, Mayer, Philip R., Dobbs, Richard, McNamara, Patrick J., Teng, Renli, Slattery, John T.
Zdroj: Pharmaceutical Research; January 1991, Vol. 8 Issue: 1 p112-118, 7p
Abstrakt: The pharmacokinetics of imirestat were studied in healthy volunteers following single and multiple oral doses. After single doses of 20 to 50 mg, imirestat plasma concentrations declined with an apparent elimination half-life of 50 to 70 hr over the 168 hr in which levels were measured. However, with lower doses (2 to 10 mg), an initial rapid decline in drug concentration was followed by a very slow terminal elimination phase with plasma concentrations decreasing little over the 1 week of sampling. This resulted in a decrease in apparent t1/2 with increasing dose, from 272 ± 138 hr at 2 mg to 66 ± 30 hr at 50 mg. During once-daily dosing of 2 to 20 nig/day for 4 weeks, mean steady-state imirestat concentrations appeared to be dose proportional, although the time required to achieve steady state decreased with increasing dose. The mean effective half-life for accumulation ranged from 54 to 98 hr, suggesting that the very slow elimination of drug at low concentrations did not produce disproportionate accumulation of drug at these doses. Mean oral clearance was independent of dose, ranging from 30 to 45 ml/min. At the 2-, 5-, and 20-mg doses, one subject in each group had steady-state concentrations two- to fourfold greater than any of the other five subjects at the same dose, although the reason for this was not apparent from these data. The overall kinetic profile of these data was suggestive of dose-dependent pharmacokinetics resulting from nonlinear tissue binding of imirestat. A two-compartment pharmacokinetic model incorporating saturable binding in the tissue compartment and elimination from the central compartment was developed and provided a good description of the plasma concentration data after both single and multiple dosing.
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