Minimal effects of two aldose reductase inhibitors, AL-1576 and AL-4114, after subacute topical-ocular dosing on xenobiotic biotransformation in rabbits

Aldose Reductase is believed to be involved in teh etiology of diabetic complications, including cataractogenesis, nephropathy, and neuropathy. AL-1576 and AL-4114, two spirohydantoin Aldose Reductase inhibitors, were specifically developed for prevention of diabetic cataractogenesis. This study has determined whether AL-1576 and AL-4114 are inducers of biotransformation by assaying the activities of some phase I and phase II Enzymes in the liver, kidney, intestine, and five ocular tissues (cornea, lens, iris-ciliary body, retina, and choroid). The Aldose Reductase inhibitors were administered topically (the intended route for use in preventing cataractogenesis) in two concentrations (0.5 and 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 benzo(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 sulfotransferase, and 1-naphthol UDP-glucuronosyltransferase were not significantly induced in the eight tissues. Clearly, ocular dosing with AL-4114 and AL-1576 for 14 days had little effect on hepatic, intestinal, and ocular biotransformation.