Aspects of pharmacodynamics and biotransformation of the glucocorticoid resocortol butyrate.
Aspects of the biotransformation and pharmacodynamics of the novel glucocorticoid resocortol butyrate (RCB) and its metabolites were assessed in vitro and in vivo in comparison with selected reference compounds. The main route of biotransformation of ((3)H)-RCB in the skin and the liver was 5alpha-reduction of the A-ring followed by reduction of the 3-carbonyl group. In the liver, metabolism was much more rapid than in the skin and 5beta-reduction also occurred. RCB had a relative binding affinity for the glucocorticoid receptor similar to that of triamcinolone acetonide, about 1.5 times that of dexamethasone, three times that of betamethasone valerate (BMV) and 10-14 times that of cortisol. The metabolites of RCB displayed only low to very low affinities for the receptor. The suppression of the hypothalamic-pituitary-adrenal axis was investigated in placebo- and positive-controlled studies in dogs by measurement of basal and corticotrophin-releasing hormone (CRH) stimulated plasma cortisol concentrations. The AUC of the plasma cortisol vs. time curve following CRH stimulation, a measure of adrenal suppression, was reduced significantly after topical application of BMV compared with the pretreatment values. The AUC in the RCB group was not reduced significantly. Adrenocorticotrophic hormone concentrations were not affected. Oral administration of RCB did not suppress adrenocortical function, whereas BMV induced almost complete suppression of basal and CRH-induced cortisol concentrations. The pharmacodynamics of RCB makes it a relatively safe glucocorticosteroid for topical application.
Coert
A
A
Intervet International BV, Boxmeer, the Netherlands.
Verheijen
F
F
Horspool
L J I
LJ
Mol
J A
JA
D000279:Administration, Cutaneous; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001711:Biotransformation; D003346:Corticotropin-Releasing Hormone; D004285:Dogs / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D008297:Male; D010913:Pituitary-Adrenal System / Q000187:drug effects; D011244:Pregnadienediols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000378:metabolism
C495826:11beta,17alpha-dihydroxy-21-methylpregna-4-diene-3,20-dione-17-butyrate; D005938:Glucocorticoids; D011244:Pregnadienediols; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone