Biotransformation of tipredane, a novel topical steroid, in mouse, rat, and human liver homogenates.
The in vitro biotransformation pathways of 3H-tipredane (3H-TP) were studied. 3H-TP, at concentrations of 1 and 250 microM, was incubated with the 10,000g supernatant fraction of the liver homogenates of mice, rats, and one human. The incubation mixtures were deproteinated with methanol and, after removal of methanol by evaporation, extracted with dichloromethane. The dichloromethane extracts were then fractionated by HPLC. 3H-TP was extensively biotransformed by the liver homogenates of the three species studied; 17 metabolites were isolated and characterized by their retention times on HPLC compared to those of the reference standards. Fourteen metabolites were identified using MS and, for some, NMR spectroscopy. Three major biotransformation pathways of TP were identified: 1) sulfoxidation, 2) elimination of the alkylthio groups, and 3) hydroxylation of the steroid nucleus. Combinations of these processes and subsequent reactions resulted in the formation of numerous metabolites whose biological activities were significantly less than that of TP. The separation of local anti-inflammatory activity from systemic side effects observed for TP in animals and humans is most probably due to its metabolic inactivation, primarily in the liver.
Lan
S J
SJ
Squibb Institute for Medical Research, Princeton, NJ 08543-4000.
Scanlan
L M
LM
Weinstein
S H
SH
Varma
R K
RK
Warrack
B M
BM
Unger
S E
SE
Porubcan
M A
MA
Migdalof
B H
BH
D000287:Administration, Topical; D000730:Androstadienes / Q000493:pharmacokinetics*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics*; D001711:Biotransformation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D008954:Models, Biological; D051381:Rats; D011919:Rats, Inbred Strains; D013454:Sulfoxides / Q000493:pharmacokinetics
D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D013454:Sulfoxides; C051756:tipredane