Pharmacokinetics and efficacy of structurally related spirohydantoin and spirosuccinimide aldose reductase inhibitors

Abstract

1. Six potent aldose reductase inhibitors (ARI), three spirohydantoin (I to III) and three spirosuccinimide (IV to VI) compounds, showed similar IC₅₀ activities in vitro for the inhibition of rat lens aldose reductase, but their ED₅₀ values in diabetic rats varied as much as 20-fold in the lens and 50-fold in the sciatic nerve tissue. Pharmacokinetic studies were undertaken to investigate these findings. Structure-pharmacokinetic relationships were studied following i.v. administration to cynomolgus monkeys.

2. The clearance (CL) of each spirosuccinimide ARI was faster (> 5 times) than that of the corresponding spirohydantoin compound. In both series the CL values of the C(4) methyl and methoxy analogues were 4-fold greater than those for the unsubstituted compounds, although the CL values of the methoxy and methyl derivatives in the same series were not significantly different.

3. The volumes of distribution (V_ss) of the spirohydantoins were about one-half those of the corresponding spirosuccinimides, and the V_ss values of the parent compounds of both ARI series did not differ dramatically from those of their methyl and methoxy analogues.

4. All six compounds were eliminated from plasma in a biexponential fashion. The half-lives (λ₁ and λ₂) of the spirohydantoin compounds were much longer than those of the corresponding spirosuccinimide compounds, and the unsubstituted compounds had longer half-lives than their methyl and methoxy derivatives. The longest λ₁ and λ₂ half-lives were observed for nirestat, while two of the spirosuccinimides had the shortest half-lives.

5. These results indicate that the relationships observed between the in vitro and in vivo activities of the six ARI can be attributed to structurally dependent differences in metabolic clearance.