Effect of Q-35, New Pyridone Carboxylic Acid, on Theophylline Metabolism in Rat Liver Microsomes

Abstract

Q-35, (±)-1-Cyclopropyl-6-fluoro-1, 4-dihydro-8-methoxy-7-(3-methylaminopiperidine-1-yl)-4-oxoquinoline-3-carboxylic acid, is a new pyridone carboxylic acid antibiotic(NQ). Certain NQs have been reported to inhibit theophylline (TP) metabolism in vivo and in vitro. We investigated the effect of Q-35 on TP metabolism by rat liver microsomes. TP was incubated with rat liver microsomes in the presence of Q-35, enoxacin, ofloxacin or ciprofloxacin. The effect of NQ was evaluated in terms of the formation of main TP metabolite, 1, 3-dimethyluric acid. Enoxacin strongly inhibited this formation while Q-35 showed the lowest inhibitory effect among four NQs.
Relationship between the structure and inhibitory effect of the Q-35 derivatives was studied. 3'-amino substituents in 7-pyperidinyl group showed a strong inhibitory activity, while the 3'-methylamino and 4'-amino substituents were weak inhibitors. Little enantiomeric effect was observed at the 3'-position. The methoxy group in the 8-position reduced inhibitory effect.
From these results, the Q-35 has little effect on TP metabolism and the effects of Q-35 derivatives on TP metabolism depends on the stereochemical stsucture of 7- and 8- substituents.