MR 714, a new aryloxypropionic non-steroidal antiinflammatory agent. Chemical and pharmacokinetic properties and preliminary pharmacotoxicological data.
2-(4-(2',4'-Difluorophenyl)-phenoxy)propionic acid (MR 714) is endowed with an interesting analgesic and antiinflammatory activity, while any remarkable gastro-ulcerogenic action is virtually absent. From a toxicological point of view, MR 714 orally administered to mice showed a LD50 of 848 mg/kg; an observation of general behaviour proved that the drug is free of any remarkable effect on general behaviour, food and water intake, or diuresis after single or repeated administration. An autoptic examination after single oral doses (25, 50, 100 and 200 mg/kg) or repeated oral doses (100 mg/kg/day over 5 days) did not show any adverse modification and also the Ames test didn't allow any mutagenic action to be detected. From a pharmacokinetic point of view, MR 714 given p.o. to rats was absorbed excellently and plasma levels showed a peak after 4-6 h, followed by a plateau lasting 24-36 h at a dose of 50 or 100 mg/kg and considerably less at a dosage of 25 mg/kg. This lower dose allowed a dominant half-life (t1/2) of plasma levels of 13 h to be determined. Excretion occurred only via the bile in conjugated form (acylglucuronide) which reverted easily into the parent drug. The resultant enterohepatic circulation contributes to a substantial maintenance of plasma levels and hence long-lasting activity. Among the organs examined, the uterus showed the highest ratio of organ/plasma concentration; this evidence points to a possible clinical application of MR 714 in the treatment of dysmenorrhoea. From a chemical point of view, the aryloxypropionic structure may be regarded as an interesting novelty in the field of structure-activity relationship studies on non-steroidal antiinflammatory agents.
D000700:Analgesics; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects; D001646:Bile / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D007700:Kinetics; D008297:Male; D051379:Mice; D009153:Mutagens; D010647:Phenyl Ethers / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000235:genetics; D013272:Stomach Diseases / Q000139:chemically induced
D000700:Analgesics; D000893:Anti-Inflammatory Agents; D009153:Mutagens; D010647:Phenyl Ethers; C037821:2-(4-(2',4'-difluorophenyl)phenoxy)propionic acid