Predicting Skin Permeability
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Published permeability coefficient (K p) data for the transport of a large group of compounds through mammalian epidermis were analyzed by a simple model based upon permeant size [molecular volume (MV) or molecular weight (MW)] and octanol/water partition coefficient (K oct). The analysis presented is a facile means to predict the percutaneous flux of pharmacological and toxic compounds solely on the basis of their physicochemical properties. Furthermore, the derived parameters of the model have assignable biophysical significance, and they provide insight into the mechanism of molecular transport through the stratum corneum (SC). For the very diverse group of chemicals considered, the results demonstrate that SC intercellular lipid properties alone are sufficient to account for the dependence of K p upon MV (or MW) and K oct. It is found that the existence of an “aqueous-polar (pore) pathway” across the SC is not necessary to explain the K p values of small, polar nonelectrolytes. Rather, their small size, and consequently high diffusivity, accounts for their apparently larger-than-expected K p. Finally, despite the size and breadth of the data set (more than 90 compounds with MW ranging from 18 to >750, and log K oct ranging from −3 to + 6), the postulated upper limiting value of K p for permeants of very high lipophilicity cannot be determined. However, the analysis is able to define the physicochemical characteristics of molecules which should exhibit these maximal K p values. Overall, then, we present a facile interpretation of a considerable body of skin permeability measurements that (a) very adequately describes the dependence of K p upon permeant size and lipophilicity, (b) generates parameters of considerable physicochemical and mechanistic relevance, and (c) implies that the SC lipids alone can fully characterize the barrier properties of mammalian skin.
- B. Idson and C. R. Behl. Drug structure vs. penetration. In Transdermal Delivery of Drugs, Vol III, A. F. Kydonieus and B. Berner (eds.), CRC Press, Boca Raton, FL, 1987, pp. 85–151.
- G. L. Flynn and B. Stewart. Percutaneous drug penetration; Choosing candidates for transdermal development. Drug Dev. Res. 13:169–185 (1988).
- C. Ackermann, G. L. Flynn, and W. M. Smith. Ether-water partitioning and permeability through hairless mouse skin in vitro. II. Hydrocortisone 21-n-alkyl esters, alkanols and hydrophilic compounds. Int. J. Pharm. 36:67–71 (1987).
- G. L. Flynn. Physicochemical determinants of skin absorption. In Principles of Route-to-Route Extrapolation for Risk Assessment, T. R. Gerrity and C. J. Henry (eds.), Elsevier, New York, 1990, pp. 93–127.
- R. J. Scheuplein and I. H. Blank. Molecular structure and diffusional processes across intact skin. Report to the US Army Chemical R&D Laboratories, Edgewood Arsenal, MD 1967.
- W. R. Lieb and W. D. Stein. Implications of two different types of diffusion for biological membranes. Nature 234:219–222 (1971).
- M. H. Cohen and D. Turnbull. Molecular transport in liquids and gases. J. Chem. Phys. 31:1164–1169 (1959).
- W. R. Lieb and W. D. Stein. Non-Stokesian nature of transverse diffusion within human red cell membranes. J. Membr. Biol. 92:111–119 (1986).
- G. B. Kasting, R. L. Smith, and E. R. Cooper. Effect of lipid solubility and molecular size on percutaneous absorption. In Skin Pharmacokinetics, B. Shroot and H. Schaefer (eds.), Karger, Basel, 1987, pp. 138–153.
- G. B. Kasting, R. L. Smith, and B. D. Anderson. Prodrugs for dermal delivery: Solubility, molecular size and functional group effects. In Prodrugs and Their Topical Use, K. B. Sloan (ed.), Marcel Dekker, New York, 1992 (in press).
- A. Bondi. van der Waals volumes and radii. J. Phys. Chem. 68:441–452 (1964).
- W. R. Lieb and W. D. Stein. Biological membranes behave as non-porous polymer sheets with respect to diffusion of nonelectrolytes. Nature 224:240–243 (1967).
- J. M. Diamond and Y. Katz. Interpretation of nonelectrolyte partition coefficients between dimyristoyl lecithin and water. J. Membr. Biol. 17:127–154 (1974).
- M. S. Roberts, R. A. Anderson, and J. Swarbrick. Permeability of human epidermis to phenolic compounds. J. Pharm. Pharmacol. 29:677–683 (1977).
- R. H. Guy and J. Hadgraft. Physicochemical aspects of percutaneous penetration and its enhancement. Pharm. Res. 5:753–758 (1988).
- D. Southwell, B. W. Barry, and R. Woodford. Variations in permeability of human skin and between specimens. Int. J. Pharm. 18:299–309 (1984).
- R. O. Potts and M. L. Francoeur. Lipid biophysics of water loss through the skin. Proc. Natl. Acad. Sci. USA 87:3871–3873 (1990).
- H. Trauble and D. H. Haynes. The volume change in lipid bilayer lamellae at the crystalline-liquid crystalline phase transition. Chem. Phys. Lipids 7:324–335 (1971).
- B. D. Anderson and P. V. Raykar. Solute structure-permeability relationships in human stratum corneum. J. Invest. Dermatol. 93:280–286 (1989).
- R. O. Potts and M. L. Francoeur. The influence of stratum corneum morphology on water permeability. J. Invest. Dermatol. 96:495–499 (1991).
- B. D. Anderson, W. I. Higuchi, and P. V. Raykar. Heterogeneity effects on permeability-partition coefficient relationships in human stratum corneum. Pharm. Res. 5:566–573 (1988).
- G. L. Flynn, H. Durrheim, and W. I. Higuchi. Permeation of hairless mouse skin. II. Membrane sectioning and influence on alkanol permeabilities. J. Pharm. Sci. 70:52–56 (1981).
- R. J. Scheuplein and I. H. Blank. Permeability of the skin. Physiol. Rev. 51:702–747 (1971).
- R. H. Guy, R. S. Hinz, and M. Amantea. Solute transport and penetration at liquid/liquid interfaces. Faraday Disc. Chem. Soc. 77:127–137 (1984).
- Pomona College Medicinal Chemistry (MEDCHEM) database. Pomona College, Claremont, CA, 1984.
- D. A. Haydon, B. M. Hendry, S. R. Levinson, and J. Requena. A comparative study of nerve impulse blockage and the properties of black lipid membranes. Biochim. Biophys. Acta 470:17–34 (1977).
- Predicting Skin Permeability
Volume 9, Issue 5 , pp 663-669
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- Kluwer Academic Publishers-Plenum Publishers
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- skin permeability
- partition coefficient
- molecular volume
- lipid lamellae
- stratum corneum
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