INVESTIGATIONS ON THE BIOTRANSFORMATION O F THE LIPOXYGENASE INHIBITOR 2-HYDROXY-5-METHYL-LAUROPHENONE-OXIME (FLM-5011)

2-Hydroxy-5-methyl-laurophenone-oxime (FLM 5011, 1) is an inhibitor of the lipoxygenase with antiinflammatory and antiallergic actions. The studies on the biotransformation using in vivo investigations and in v itro test systems resulted in finding of at least eight metabolites. F our of these compounds have been detected and identified in urine and faeces after p.o. administration in male Wistar rats. By means of cult ures of hepatocytes, lymphocytes and myeloma cells additional metaboli tes were found and the main pathways of metabolism could be suggested. Furthermore it was possible to confirm the sequence of the metabolic reactions. First of all, 1 is hydroxylated in the omega-position of th e lauryl side chain by the cytochrom P-450 system. The further oxidati on to the carboxylated compound is followed by the stepwise degradatio n of the side chain by beta-oxidation similarly to the pathways of fat ty acid metabolism. Simultaneously the oxime group is converted to the keto group, The metabolites and 1 partly occur as sulfate or glucuron ide conjugates. Additionally all compounds produced by beta-oxidation are conjugated with other partners, probably amino acids. By omega-oxi dation, compounds with higher inhibitory potency on the lipoxygenase t han the parent compound are formed. These results suggest that the act ivity of 1 is partly caused by the initial metabolites.