Pharmacokinetics and efficacy of structurally related spirohydantoin and spirosuccinimide aldose reductase inhibitors.
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 (greater than 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 (Vss) of the spirohydantoins were about one-half those of the corresponding spirosuccinimides, and the Vss 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 (lambda 1 and lambda 2) 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 lambda 1 and lambda 2 half-lives were observed for imirestat, 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.
Park
Y H
YH
Research and Development, Alcon Laboratories, Inc., Fort Worth, Texas 76134.
Barker
R
R
Griffin
B
B
Barratt
D
D
DuPriest
M
M
Brazzell
K
K
York
B
B
Mayer
P
P
D000284:Administration, Oral; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D003459:Crystallins / Q000037:antagonists & inhibitors; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism; D005260:Female; D005449:Fluorenes / Q000493:pharmacokinetics / Q000494:pharmacology; D006827:Hydantoins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D007275:Injections, Intravenous; D007649:Ketamine / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
D003459:Crystallins; D005449:Fluorenes; D006827:Hydantoins; D013141:Spiro Compounds; D013388:Succinimides; C052241:imirestat; D007649:Ketamine; D000449:Aldehyde Reductase