The role of corneocytes in skin transport revised--a combined computational and experimental approach.
OBJECTIVE
To investigate mechanisms of compound-corneocyte interactions in a combined experimental and theoretical approach.


METHODS
Experimental methods are presented to investigate compound-corneocyte interactions in terms of dissolution within water of hydration and protein binding and to quantify the extent of the concurrent mechanisms. Results are presented for three compounds: caffeine, flufenamic acid, and testosterone. Two compartmental stratum corneum models M1 and M2 are formulated based on experimentally determined input parameters describing the affinity to lipid, proteins and water. M1 features a homogeneous protein compartment and considers protein interactions only via intra-corneocyte water. In M2 the protein compartment is sub-divided into a cornified envelope compartment interacting with inter-cellular lipids and a keratin compartment interacting with water.


RESULTS
For the non-protein binding caffeine the impact of the aqueous compartment on stratum corneum partitioning is overestimated but is successfully modeled after introducing a bound water fraction that is non-accessible for compound dissolution. For lipophilic, keratin binding compounds (flufenamic acid, testosterone) only M2 correctly predicts a concentration dependence of stratum corneum partition coefficients.


CONCLUSIONS
Lipophilic and hydrophilic compounds interact with corneocytes. Interactions of lipophilic compounds are probably confined to the corneocyte surface. Interactions with intracellular keratin may be limited by their low aqueous solubility.
Hansen
Steffi
S
Department of Biopharmaceutics and Pharmaceutical Technology, Saarland University, Saarbruecken, Germany.
Naegel
Arne
A
Heisig
Michael
M
Wittum
Gabriel
G
Neumann
Dirk
D
Kostka
Karl-Heinz
KH
Meiers
Peter
P
Lehr
Claus-Michael
CM
Schaefer
Ulrich F
UF
D001692:Biological Transport; D002110:Caffeine / Q000378:metabolism / Q000493:pharmacokinetics*; D000078404:Epidermal Cells; D004817:Epidermis / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D005439:Flufenamic Acid / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D007633:Keratins / Q000032:analysis / Q000378:metabolism; D008055:Lipids / Q000032:analysis; D008954:Models, Biological; D011485:Protein Binding; D012869:Skin Absorption; D012995:Solubility; D013739:Testosterone / Q000378:metabolism / Q000493:pharmacokinetics*; D014867:Water / Q000032:analysis / Q000378:metabolism
D008055:Lipids; D014867:Water; D002110:Caffeine; D013739:Testosterone; D005439:Flufenamic Acid; D007633:Keratins