RT Journal Article
SR Electronic
T1 Minimal effects of two aldose reductase inhibitors, AL-1576 and AL-4114, after subacute topical-ocular dosing on xenobiotic biotransformation in rabbits.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1094
OP 1098
VO 23
IS 10
A1 Sastry, S G
A1 Sanders, R A
A1 Veltman, J C
A1 Watkins, J B
YR 1995
UL http://dmd.aspetjournals.org/content/23/10/1094.abstract
AB 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.