Comparative Anatomical Factors Affecting Topical Delivery

Transcription

1 Comparative Anatomical Factors Affecting Topical Delivery Nancy A. Monteiro-Riviere, Ph.D., Fellow ATS Professor of Investigative Dermatology and Toxicology Center for Chemical Toxicology Research and Pharmacokinetics Department of Clinical Sciences College of Veterinary Medicine North Carolina State University Raleigh, NC, 27606, USA Phone: (919) Fax: (919)

2 Why talk about skin? Most visible organ in the body Complexity of biology inherent to this barrier organ is often underestimated Target of multi-billion dollar cosmetic industry Skin is also a portal for entry of topically applied chemicals

3 Biological Functions of Skin Physical and metabolic barrier to the environment : stratum corneum Thermoregulation : hair and fur, apocrine and eccrine sweat glands, sebaceous glands and blood flow shunts Mechanical Support : collagen and water Endocrine (e.g., vitamin D) Neurosensory reception Immunologic responses : keratinocytes, Langerhans cells Metabolism, Biotransformation Uniquely exposed to UV light sunburn

4 Cutaneous Biotransformation Although P450 activity is less in skin, it can have a profound effect on bioavailability Phase I and II occur in basal layer Applications Prodrugs: conversion of lipid ester to free drug detoxification of pesticides (parathion) bioactivation of toxicants (benzo(a)pyrene) Minimal work published on species differences in absorption related to biotransformation!

5 Overview Potential pathways for absorption Species differences Regional differences Experimental model systems Disease and alteration of the barrier

6 Monteiro-Riviere NA: Comparative Anatomy, Physiology, and Biochemistry of Mammalian Skin. In Dermal and Ocular Toxicology: Fundamentals and Methods (Ed. DW Hobson). CRC Press, Inc., New York, New York, Chapter 1, pp. 3-71, 1991.

7

8 Anatomical Considerations Primary barrier to drug absorption is the stratum corneum Composed of dead keratinocytes embedded in a lipid matrix, through which most drugs are absorbed Lipid matrix excreted by cells in lower layer Basal layer consists of viable keratinocytes which migrate to surface and are ultimately shed. Other cell types present:melanocytes, Merkel cells, Langerhans cells, etc.) Dermis and vasculature

9

10 Menon and Fartasch. Structure and Functional Correlations of Skin Barrier. In Toxicology of the Skin-Target Organ Series. (Ed. NA Monteiro-Riviere). Informa Healthcare, NY, Vol. 29, Chapt. 10, , 2010.

11 Menon and Fartasch. Structure and Functional Correlations of Skin Barrier. In Toxicology of the Skin-Target Organ Series. (Ed. NA Monteiro-Riviere). Informa Healthcare, NY, Vol. 29, Chapt. 10, , 2010.

12 Monteiro-Riviere NA. Structure and Function of Skin. In Toxicology of the Skin-Target Organ Series. (Ed. NA Monteiro-Riviere). Informa Healthcare, NY, Vol. 29, Chapter 1, 1-18, 2010.

13 Monteiro-Riviere NA. Structure and Function of Skin. In Toxicology of the Skin-Target Organ Series. (Ed. NA Monteiro-Riviere). Informa Healthcare, NY, Vol. 29, Chapter 1, 1-18, 2010.

14 Interactions Between Solutes and Intercellular Lipids Grice, Zhang, Roberts. Chemical Structure- Skin Transport Relationships. In Toxicology of the Skin-Target Organ Series. (Ed. NA Monteiro-Riviere). Informa Healthcare, NY, Vol. 29, Chapt. 6, 55-68, 2010.

15 Composition and Orientation of Stratum Corneum Lipids are Important Determinants of Barrier Function

16 Skin: PORTAL of Entry and TARGET for Toxicity IL-8, TNF α, Others SYSTEMIC EFFECT

17 Monteiro-Riviere NA and Riviere JE: Skin Toxicology In Toxicology, (Eds. H Marquardt, S Schafer, R McClellan, F Welsch), Academic Press, San Diego, CA, Chapt. 18, , 1999.

18 Target for immune localization and potential lymphatic transport are Langerhans cells located just beneath stratum corneum Absorption pass the epidermis is NOT required for a toxicological response. The same can be said for skin carcinogens.

19 AUTOPOIESIS Menon and Fartasch. Structure and Functional Correlations of Skin Barrier. In Toxicology of the Skin-Target Organ Series. (Ed. NA Monteiro-Riviere). Informa Healthcare, NY, Vol. 29, Chapt. 10, , 2010.

20 Dancik, Thompson, Krishnan, Roberts. Cutaneous Metabolism and Active Transport in Transdermal Drug Delivery. In Toxicology of the Skin-Target Organ Series. (Ed. NA Monteiro-Riviere). Informa Healthcare, NY, Vol. 29, Chapt. 7, 69-82, 2010.

21 Importance of Lipid Biochemistry/ Biophysics Removal of rate-limiting stratum corneum increases absorption Intercellular lipids are the primary pathway for drug absorption Consist primarily of ceramides, sterols, and other neutral lipids Exist in a liquid-crystalline matrix, the fluidity of which is related to permeability of hydrophilic drugs Temperature, hydration and chemical penetration enhancers increase fluidity and permeability

22 Absorption Relates to the amount of chemical that penetrates the skin and then absorbed into the bloodstream to have a systemic effect. Detected by flux into the perfusate or blood. Penetration Relates to the amount of chemical that gets to targets within the skin and could be available for local cutaneous activity. Detected by confocal microscopy, transmission electron microscopy, special stains, biopsies and tape stripping.

23 Monteiro-Riviere NA: Structure and Function of Skin. In Dermal Absorption Models in Toxicology and Pharmacology (Ed. JE Riviere). CRC, Taylor and Francis, Boca Raton, FL. Chapter 1. pp. 1-19, 2006.

24 Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman s Textbook of Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6 th ed., pp , 2006.

25 Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman s Textbook of Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6 th ed., pp , 2006.

26 Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman s Textbook of Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6 th ed., pp , 2006.

27 Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman s Textbook of Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6 th ed., pp , 2006.

28 Monteiro-Riviere NA. Ultrastructural Evaluation of the Porcine Integument. In Swine in Biomedical Research, Tumbleson ME (ed), NY, Plenum Press, vol 1.pp , 1986.

29 Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman s Textbook of Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6 th ed., pp , 2006

30 Monteiro-Riviere NA. Structure and Function of Skin. In Toxicology of the Skin-Target Organ Series. (Ed. NA Monteiro-Riviere). Informa Healthcare, NY, Vol. 29, Chapter 1, 1-18, 2010.