Skin penetration and metabolism of topical glucocorticoids in reconstructed epidermis and in excised human skin.
OBJECTIVE
To investigate pharmacokinetic differences between the nonhalogenated double ester prednicarbate (PC) and the fluorinated monoester betamethasone 17-valerate (BM17V) their metabolism in human keratinocytes and fibroblasts as well as their permeation and biotransformation in reconstructed epidermis and excised human skin was compared. Special attention was given to the 17-monoesters because of their high receptor affinity and antiproliferative effects.


METHODS
Glucocorticoid penetration was determined using Franz diffusion cells, quantifying metabolite concentrations by HPLC. Chemical stability and reactivity of the monoesters was determined by molecular modeling analysis.


RESULTS
PC accumulated in the stratum corneum. A considerable amount of penetrating PC was hydrolyzed by viable keratinocytes to prednisolone 17-ethylcarbonate (PI7EC), P17EC permeated the skin very rapidly when compared to BM17V. Overall P17EC concentrations in viable tissue were low. Inside of the acceptor fluid, but not within the tissue, P17EC was converted to the more stable prednisolone 21-ethylcarbonate (P21EC).


CONCLUSIONS
The inactivation of highly potent, but also cell toxic, 17-monoesters to almost inactive 21-congeners seen with isolated cell monolayers appears less important in the skin. In vitro determination of the dermal 17-monoesters concentrations may allow the prediction of the atrophogenic risk in man. BM17V levels exceeding P17EC concentration about 6-fold may contribute to its lower tolerance when compared to PC.
Gysler
A
A
Institut für Pharmazie, Abteilung für Pharmakologie und Toxikologie, Freie Universität Berlin, Germany.
Kleuser
B
B
Sippl
W
W
Lange
K
K
Korting
H C
HC
Höltje
H D
HD
Korting
H C
HC
D000287:Administration, Topical; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001624:Betamethasone Valerate / Q000378:metabolism / Q000493:pharmacokinetics; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects* / Q000201:enzymology*; D004950:Esterases / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005938:Glucocorticoids; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009824:Ointments / Q000378:metabolism / Q000493:pharmacokinetics; D011239:Prednisolone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D018570:Risk Assessment; D012869:Skin Absorption / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D009824:Ointments; D001624:Betamethasone Valerate; D011239:Prednisolone; D004950:Esterases; C035287:prednicarbate