Absorption and metabolism of hydrocortisone 21-butyrate, 21-hemisuccinate and hydrocortisone by skin of the rabbit ear during single-pass perfusion.
1. Rabbit ear was single-pass perfused with protein-free buffer solution at a rate of 0.02 ml/min per cm2 surface area for up to 6 h. 2. Hydrocortisone or hydrocortisone 21-butyrate or hydrocortisone 21-hemisuccinate was applied dermally (0.01-1.0% w/w) in suspension with isopropyl myristate or dissolved in 1,2-propanediol. The ointments were stiffened with 5% polyethylene 1500 or 1.2% methylcellulose respectively. 3. Hydrocortisone was slowly absorbed and did not reach a steady-state absorption rate during the experimental period. 4. No metabolites of hydrocortisone were found during ear perfusion. In the supernatant of skin homogenate, however, cortisone, hydrocortisone-20 alpha-ol and another, as yet unidentified metabolite, were observed. 5. Hydrocortisone 21-butyrate was completely hydrolysed during dermal absorption, showing steady-state concentrations of hydrocortisone in the effluent. Hydrocortisone 21-hemisuccinate did not reach steady-state concentrations in the effluent. About two-thirds was hydrolysed during absorption. 6. During arterial perfusion approximately 30% of hydrocortisone 21-butyrate was hydrolysed whereas 97% of hydrocortisone 21-hemisuccinate remained intact. 7. First-pass ester hydrolysis in skin may be complete for the poorly absorbed glucocorticoids leading to metabolites of less lipophilicity.
Bast
G E
GE
Walther-Straub-Institute for Pharmacology und Toxicology, Faculty of Medicine Ludwig-Maximilians-University, Munich, Germany.
Kampffmeyer
H G
HG
D000042:Absorption; D000279:Administration, Cutaneous; D000818:Animals; D004423:Ear; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D007700:Kinetics; D009226:Myristates; D010477:Perfusion; D019946:Propylene Glycol; D011409:Propylene Glycols; D011817:Rabbits; D012867:Skin / Q000378:metabolism*
D009226:Myristates; D011409:Propylene Glycols; C008205:isopropyl myristate; D019946:Propylene Glycol; C007133:hydrocortisone hemisuccinate; D006854:Hydrocortisone; C033015:hydrocortisone 21-butyrate