Effect of some biologically interesting substituted tetrahydro-1,4-oxazines on drug metabolising enzymes and on inflammation.
The effect on hepatic drug metabolising enzymes was evaluated for three representative structures and that were selected from a series of substituted oxazine derivatives designed to possess particular pharmacological properties such as analgesic, antioxidant and hypolipidemic activity. In addition, since xenobiotic metabolism, reactive oxygen and nitrogen species, atherosclerosis and inflammation are interrelated and mutually affected, the effects of and on acute inflammation in vivo and lipoxygenase activity in vitro were also investigated. It was found that treatment of rats with caused induction of cytochrome P450, enhancement of the metabolism of aminopyrine in vitro and of zoxazolamine and hexobarbital in vivo. Compound appeared to induce particularly erythromycin N-demethylation, while, a nitric ester, reduced the catalytically active cytochrome P450, although it increased the metabolism of specific cytochrome P450 substrates, i.e. 4-nitrophenol and erythromycin. Compounds and with strong hypolipidemic and antioxidant properties, reduced acute inflammatory response in two inflammation models and inhibited lipoxygenase activity in vitro. These results are helpful in optimising the biological profile as well as the potential applications of substituted oxazines.
Rekka
E A
EA
Department of Medicinal Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, Thessaloniki 54124, Greece. rekka@pharm.auth.gr
Kourounakis
A P
AP
Avramidis
N
N
Kourounakis
P N
PN
D000818:Animals; D000893:Anti-Inflammatory Agents; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004791:Enzyme Inhibitors; D005620:Freund's Adjuvant; D000960:Hypolipidemic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D007928:Lethal Dose 50; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D009569:Nitric Oxide / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats
D000893:Anti-Inflammatory Agents; D000924:Anticholesteremic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D016859:Lipoxygenase Inhibitors; D009025:Morpholines; D004364:Pharmaceutical Preparations; D009569:Nitric Oxide; D005620:Freund's Adjuvant; D003577:Cytochrome P-450 Enzyme System