Cytochrome P4501A(CYP1A) induction in rat and man by the benzodioxino derivative, fluparoxan

1. Fluparoxan is an α2-adrenoceptor antagonist that has a relatively planar, tricyclic structure and was considered a potential substrate and inducer of cytochrome P4501A (CYP1A) enzymes. 2. Structure-activity analysis indicated some potential for CYP1A interaction, although its greater log P and molecular depth, compared with many CYP1A inducers, suggested fluparoxan would be a weak ligand for the aryl hydrocarbon (Ah) receptor and only a weak inducer. 3. In vitro, fluparoxan showed little affinity for the CYP1A enzymes. The compound was not metabolized by human CYP1A1 or 1A2 heterologously expressed in yeast and its rate of metabolism in rat and human microsomes was unaffected by the addition of the 1A inhibitor α-naphthoflavone. Furthermore, Ki's for fluparoxan against EROD activity were >4000-fold higher than those of α-naphthoflavone. 4. In vivo, however, fluparoxan did show some capacity for CYP1A induction. In rat, hepatic EROD activity increased approximately 40- fold with seven once-daily oral doses of fluparoxan (50 mg kg, solution), and immunoblotting studies confirmed induction of CYP1A2, though not of 1A1. In man, administration of 11 twice-daily oral doses of fluparoxan (8 mg tablet) produced some reduction in plasma levels of orally administered phenacetin and in the ratio of phenacetin AUC urinary paracetamol, consistent with increased O-deethylation.