New potent modifiers of liver microsomal drug metabolism: 1- Arylimidazoles.
Drug Metab Dispos 1973 Nov; 1(6):775-779
The effects of 1-(2-isopropylphenyl)imidazole (25364403) (IPI) and 1- (2-cyanophenyl)imidazole (25373493) (CPI) on liver microsomal drug metabolism were studied in-vivo and in-vitro. Liver microsomes from male Holtzman-rats, some of which had been pretreated with sodium- phenobarbital, were incubated with IPI or CPI. The effects on aniline-p-hydroxylase, acetanilide-hydroxylase, and aminopyrine-N- demethylase activity were investigated. IPI was added to oxidized or reduced liver microsomes and the difference spectra were recorded. Rat liver microsomes were treated with IPI and metyrapone and the effects on epoxide-hydrase activity using cyclohexene-oxide and styrene-oxide as substrates were determined. Rats were treated with IPI and metyrapone and the effects on hexobarbital sleeping time were assessed. IPI and CPI competitively inhibited aniline-p- hydroxylase and acetanilide-hydroxylase and noncompetitively inhibited aminopyrine-N-demethylase, IPI being the more potent. IPImg/kg prolonged hexobarbital sleeping time from 70.3 to 379.1 minutes. The central nervous system (CNS) depression was so great that two of six rats died. Metyrapone at 60mg/kg caused a similar hexobarbital sleeping time but without the CNS depression. IPI significantly stimulated epoxide-hydrase for both cyclohexene-oxide and styrene-oxide, its effect being much greater than that of metyrapone. IPI formed a type-II difference spectrum, peak at 430 nanometers (nm) and trough at 394nm, when added to oxidized microsomes. The spectrum was not significantly affected by pH. When added to reduced microsomes, a spectrum with two peaks, at 423 and 450nm, was obtained. The 450nm peak became prominent at high pH values. The authors conclude that IPI is the most potent inhibitor of mammalian liver microsomal drug metabolizing systems yet described.
NIOSH-Publication; NIOSH-Grant; Grants-other; In-vivo-studies; In-vitro-studies; Drugs; Laboratory-animals; Liver-microsomal-metabolism; Absorption-spectrophotometry
Pharmacology and Therapeutics Univ of Florida Coll of Med Dept of Pharma & Therapeutics Gainesville, Fla 32601
Other Occupational Concerns; Grants-other
Drug Metabolism and Disposition
University of Florida Gainesville, Gainesville, Florida