Does solute stereochemistry influence percutaneous penetration?
The stratum corneum, the rate-limiting barrier to percutaneous penetration, is made up of several components, principally keratin and ceramides. These are potential sources of chiral discrimination that could result in differential diffusion rates, dependent upon the stereochemistry of the solute. Although binding to keratin can occur it is not a stereoselective process [percent binding to solubilised epidermal keratin: (R)-propranolol 7.9 +/- 1.7, (S)-propranolol 8.3 +/- 2.0]. On the other hand, studies with ceramide monolayers produced qualitative evidence of dose-dependent stereoselective interaction when the pure diastereomers of ephedrine were present in the aqueous subphase which suggested that differences in diffusion rates might occur in skin. However, the differences in permeation rates in vitro for these diastereomers through human skin were not statistically different [(+)-(1S,2R)-ephedrine 119.1 +/- 2.6 micrograms/cm2, (-)-(1R,2S)-ephedrine 107.0 +/- 3.9 micrograms/cm2, 12 h]. Time averaging, involving contributions from binding to all lipid headgroups present in the intercellular channels, may obscure specific differential interactions. Further, any stereospecific interaction may be subtle and readily overwhelmed if diffusant concentration is greater than the capacity of the skin to differentiate between stereoisomers. Evidence for intrinsic stereoselectivity in skin permeation has therefore yet to be obtained.
Heard
C M
CM
Welsh School of Pharmacy, University of Wales College of Cardiff, United Kingdom.
Brain
K R
KR
D002518:Ceramides / Q000737:chemistry / Q000378:metabolism*; D004809:Ephedrine / Q000493:pharmacokinetics; D006801:Humans; D007633:Keratins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D012867:Skin / Q000737:chemistry*; D012869:Skin Absorption / Q000502:physiology*; D013237:Stereoisomerism; D013816:Thermodynamics
D002518:Ceramides; D007633:Keratins; D004809:Ephedrine