Biological activity of the main metabolites of meloxicam.
Meloxicam (Mel) is a new non-steroidal anti-inflammatory drug (NSAID) which was selected with regard to its remarkable efficacy in adjuvant arthritis of the rat. Similar to the situation in man, three main metabolites were identified in rat urine which are rapidly excreted since they are not detectable in blood, where only the parent compound was found. The latter is practically not eliminated in urine. Since it has been proposed that the nephrotoxicity of NSAIDs is due to inhibition of prostaglandin E2 (PG) biosynthesis, the aim of the study was to determine whether the metabolites can contribute to the known effects of the parent compound in this pathway. For this purpose, PG-biosynthesis was measured in vitro using a radiochemical technique with an enzyme preparation from bull seminal vesicles. In an in vivo assay the effect of the compounds against kaolin-induced oedema in the rat hind paw was determined. In the test systems described, the efficacy of Mel has been demonstrated. In contrast to this finding, the metabolites in relevant doses showed neither in vitro nor in vivo effects. From the results it can be concluded that the metabolites do not change renal blood flow and therefore have no capability for nephrotoxicity. These findings are in accordance with the observations in the rat kidney during subacute and chronic toxicity studies, where no nephrotoxic effects could be detected after therapeutic doses.
Engelhardt
G
G
Department of Pharmacology, Dr Karl Thomae GmbH, Biberach/Riss, FRG.
Trummlitz
G
G
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005122:Exudates and Transudates / Q000187:drug effects; D007616:Kaolin; D008297:Male; D000077239:Meloxicam; D011453:Prostaglandins / Q000096:biosynthesis; D051381:Rats; D013843:Thiazines / Q000378:metabolism* / Q000494:pharmacology; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011453:Prostaglandins; D013843:Thiazines; D013844:Thiazoles; D007616:Kaolin; D000077239:Meloxicam