Pharmacokinetics

The development of aldose reductase inhibitors as useful drugs is actually at the stage of evaluation of their pharmacodynamic benefit. Data on the pharmacokinetic properties of these drugs are therefore rather scarce. In addition, owing to their chemical heterogeneity, no common principles can be established.

4.1 absorption

Tolrestat is absorbed after oral administration to the extent of about 70% in man. Data on different animal models give higher values (Dvornik et al., 1988).

4.2 plasma levels

The maximal plasma level after a single oral dose of 100 mg tolrestat is about 5-8/i.gml-1 which is reached after about 2h. Multiple oral dosing (twice daily) results in a steady state after 6 days, and no unexpected accumulation occurs, yielding linear pharmacokinetics even during chronic dosing (data from Wyeth-Ayerst Int. Inc.).

4.3 distribution

The plasma protein binding of tolrestat is very high, only 0.7% of the drug being free in the plasma. No competition exists with warfarin, but to some extent with high concentrations of tolbutamide or salicylate (Moulds et al., 1991).

4.4 half-life

The plasma half-life of tolrestat after a single dose is about 10-13 h in both healthy and diabetic volunteers (Hicks et al., 1984).

4.5 elimination

About 70% of tolrestat is eliminated via the kidneys, of which about 60% is unchanged. About one-quarter of a dose can be recovered in the faeces. Tolrestat is metabolized to oxo-tolrestat and sulpho-tolrestat (Wyeth-Ayerst Int. Inc.).

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