Rapid metabolic inactivation of tipredane, a structurally novel topical steroid.
[3H]Tipredane ([3H]TP), [3H]triamcinolone acetonide ([ 3H]TAAC), [3H]hydrocortisone ([3H]HC), and [3H]betamethasone-17 alpha-valerate ([3H]BMV), each at a concentration of 1 microM, were separately incubated with the 10,000 g supernatant fraction of the liver and skin homogenates of humans, rats and mice (BMV was studied only in human liver). Sequential samples were taken for up to 1 h during each incubation. The radioactivity in each sample was extracted with methanol, and the methanolic extracts were analyzed by high performance liquid chromatography. Among the four compounds studied, [3H]TP was most rapidly biotransformed by the liver preparations of the three species. The rates of in vitro biotransformation of TP were 2.5-30 times faster than those of TAAC, HC and BMV. In the human liver preparation, the rates of biotransformation were in the order of: TP greater than TAAC greater than HC = BMV. In the mouse and rat liver preparations, the orders were: TP greater than TAAC greater than HC and TP greater than HC greater than TAAC, respectively. In the skin preparations, little, if any, biotransformation of [3H]TP and [3H]TAAC was observed in any of the species studied; however, [3H]HC underwent a slow, steady biotransformation in the skin preparations of humans and rats but not of mice. [3H]TP was biotransformed by the liver preparations of all three species to numerous metabolites, thirteen of which have been identified. The biotransformation reactions included: (1) sulfoxidation; (2) elimination of either one or both alkylthio groups; and (3) hydroxylation of the steroid nucleus. Some metabolites were synthesized and tested for glucocorticoid receptor binding and anti-inflammatory activities; all were found to be much less potent than TP. The observed separation of local anti-inflammatory activity from systemic side effects of TP is most probably due to its rapid metabolic inactivation; the liver, rather than the skin, is mainly responsible for the metabolic inactivation of TP.
Lan
S J
SJ
Squibb Institute for Medical Research, Princeton, NJ 08543-4000.
Scanlan
L M
LM
Mitroka
J
J
Weinstein
S H
SH
Lutsky
B N
BN
Free
C A
CA
Wojnar
R J
RJ
Millonig
R C
RC
Migdalof
B H
BH
D000730:Androstadienes / Q000378:metabolism*; D000818:Animals; D001624:Betamethasone Valerate / Q000378:metabolism; D001711:Biotransformation; D006207:Half-Life; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism; D051379:Mice; D051381:Rats; D012867:Skin / Q000378:metabolism; D014222:Triamcinolone Acetonide / Q000378:metabolism
D000730:Androstadienes; C051756:tipredane; D001624:Betamethasone Valerate; D014222:Triamcinolone Acetonide; D006854:Hydrocortisone