title: Minimal effects of two aldose reductase inhibitors, AL-1576 and AL-4114, after subacute topical-ocular dosing on xenobiotic biotransformation in rabbits.
abstract: 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.
authors.affiliation: Medical Sciences Program, Indiana University School of Medicine, Bloomington 47405-4401, USA.
authors.forename: S G
authors.initials: SG
authors.lastname: Sastry
authors.forename: R A
authors.initials: RA
authors.lastname: Sanders
authors.forename: J C
authors.initials: JC
authors.lastname: Veltman
authors.forename: J B
authors.initials: JB
authors.lastname: Watkins
mesh_terms: D000287:Administration, Topical; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001711:Biotransformation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005123:Eye / Q000378:metabolism*; D005449:Fluorenes / Q000494:pharmacology*; D006827:Hydantoins / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D011817:Rabbits; D013141:Spiro Compounds / Q000494:pharmacology*; D015262:Xenobiotics / Q000493:pharmacokinetics*
chemical_list: D004791:Enzyme Inhibitors; D005449:Fluorenes; D006827:Hydantoins; D013141:Spiro Compounds; D015262:Xenobiotics; C052241:imirestat; C079554:AL 4114; D000449:Aldehyde Reductase