[Biotransformation of 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 vitro test systems resulted in finding of at least eight metabolites. Four of these compounds have been detected and identified in urine and faeces after p.o. administration in male Wistar rats. By means of cultures of hepatocytes, lymphocytes and myeloma cells additional metabolites 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 the lauryl side chain by the cytochrome P-450 system. The further oxidation to the carboxylated compound is followed by the stepwise degradation of the side chain by beta-oxidation similarly to the pathways of fatty acid metabolism. Simultaneously the oxime group is converted to the keto group. The metabolites and 1 partly occur as sulfate or glucuronide conjugates. Additionally all compounds produced by beta-oxidation are conjugated with other partners, probably amino acids. By omega-oxidation, compounds with higher inhibitory potency on the lipoxygenase than the parent compound are formed. These results suggest that the activity of 1 is partly caused by the initial metabolites.
Langner
A
A
Institut für Pharmazie, Humboldt-Universität zu Berlin, Germany.
Rentsch
C
C
Nerlich
C
C
Rittner
I
I
Kühn
H
H
Schewe
T
T
Franke
P
P
D000818:Animals; D001711:Biotransformation; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D005243:Feces / Q000737:chemistry; D007850:Lauric Acids; D016859:Lipoxygenase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D008099:Liver / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D010091:Oximes; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
D007850:Lauric Acids; D016859:Lipoxygenase Inhibitors; D010091:Oximes; C059535:FLM 5011
Untersuchungen zur Biotransformation des Lipoxygenasehemmers 2-Hydroxy-5-methyl-laurophenon-oxim (FLM 5011).