Effects of Aldose Reductase Inhibitors, Al-4114 and Al-1576, on Hepatic Biotransformation in Rabbit and Rat

Abstract

Aldose reductase is part of the sorbitol pathway, which has been linked to many diabetic complications such as retinopathy and cataracts. This study has determined whether two aldose reductase inhibitors, AL-1576 and AL-4114, may be inducersof hepaticbiotransformation in New Zealandwhiterabbits or Sprague-Dawley rats. The drugs were administered either by intraperitoneal injection (ip) once a day for 4 days (10 mg/kg or 50 mg/kg) to rats and rabbits or by topical-ocular dosing three times a day for 14 days to rabbits (0.5% or 5.0%). Rats dosed ip had increased hepatic cytochrome P450 monooxygenase activity toward methoxy count ar in and benzphetamine, glutathione S-transferase activity toward 1-chloro-2,4-dinitrobenzene, and uridine diphosphate (UDP)-glucurono-syltr an sferase activity toward 4-hydroxybiphenyl and 1-naphthol. In rabbits, ip dosing increased only glucuronosyltransferase activity toward 4-hydroxybiphenyl after AL-4114, and no hepatic biotr an sformation enzyme activities were increased after topical-ocular dosing with either AL-4114 or AL-1576. Activities of other enzymes, including P-450 monooxygenase toward benzo(a)pyrene, N-acetyltr an sferase toward 2-aminofluorene and β-naphthylamine, UDP-glucuronosyltransferase toward 4-methylumbelliferone, styreneoxidehydrolase, and 2-naphthol suIfotransferase, were not increased by either topical-ocular or ip dosing with AL-1576 or AL-4114 in either rats or rabbits, although ip dosing with AL-1576 decreased monooxygenase activity toward ethoxyresorufin in rabbit liver. These results indicate that AL-1576 and AL-4114, though inducers of hepatic biotr an sformation in rats, do not induce hepatic biotran sformation in rabbits when administered by either ip or topical-ocular dosing.