Interaction of the Imidazolone Derivative GPA 1851 with Hepatic Microsomal Drug Metabolism

Abstract

The biological disposition of GPA 1851, a compound with anti-inflammatory proper ties, has been investigated in several species. During these studies a dramatic prolongation of barbitu rate sleeping time was observed in rats, dogs and monkeys pretreated with GPA 1851. Both in vivo and in vitro findings indicated that the interaction of GPA 1851 with barbiturates was a result of its inhibition of hepatic microsomal enzyme activity. However, further studies demonstrated that repeated dosing with GPA 1851 abolished the inhibitory effect of a single dose.

High-Performance Liquid Chromatographic Studies of Reaction of Hydralazine with Biogenic Aldehydes and Ketones

“…Hydralazine was reported to condense in uiuo with ketones to form hydrazones (2,4,5). While the details are not well understood, the first step was to assess the effect of the individual aldehydes and ketones on the overall formation of different hydrazones with hydralazine.…”

“…Hydrazone formation is important for investigating hydralazine toxicity and alterations in hydralazine metabolism and pharmacokinetics. While hydrazone formation has been evaluated in uiuo (1)(2)(3)(4)(5), no supporting chemical studies have been reported.…”

Differential Effects of GPA 1851 on Hepatic Microsomal Drug Metabolism Dependent on Dosage and Time of Sacrifice

“…During testing in animals it was observed that pretreatment with large doses of GPA 1851 potentiated the response to intravenous pento barbital and hexobarbital by prolonging sleeping times (Zak et al, 1972). The following experiments were performed to elucidate the mechanism whereby GPA 1851 enhanced the effect of barbiturates.…”