MINIMAL EFFECTS OF 2 ALDOSE REDUCTASE INHIBITORS, AL-1576 AND AL-4114, AFTER SUBACUTE TOPICAL-OCULAR DOSING ON XENOBIOTIC BIOTRANSFORMATIONIN RABBITS

Aldose reductase is believed to be involved in the etiology of diabeti c complications, including cataractogenesis, nephropathy, and neuropat hy. AL-1576 and AL-4114, two spirohydantoin aldose reductase inhibitor s, were specifically developed for prevention of diabetic cataractogen esis. This study has determined whether AL-1576 and AL-4114 are induce rs of biotransformation by assaying the activities of some phase I and phase II enzymes in the liver, kidney, intestine, and five ocular tis sues (cornea, lens, iris-ciliary body, retina, and choroid). The aldos e reductase inhibitors were administered topically (the intended route for use in preventing cataractogenesis) in two concentrations (0.5 an d 5.0%) each 3 times/day to both eyes of New Zealand white rabbits for 14 days. Lenticular aldose reductase activity was decreased by 30-75% by the aldose reductase inhibitors. Monooxygenase activity toward ben zo(a)pyrene, ethoxyresorufin, and methoxycoumarin was not increased by AL-1576 or AL-4114 treatment in any tissue, Activities of 1-chloro-2, 4-dinitrobenzene glutathione S-transferase, 2-naphthol sulfotransferas e, and 1-naphthol UDP-glucuronosyltransferase were not significantly i nduced in the eight tissues. Clearly, ocular dosing with AL-4114 and A L-1576 for 14 days had little effect on hepatic, intestinal, and ocula r biotransformation.