Monteiro-Riviere NA - College of Veterinary Medicine

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) 513-6426 Fax: (919) 513-6358
Nancy_Monteiro@ncsu.edu

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

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

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!

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

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.

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

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, 110-130, 2010.

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, 110-130, 2010.

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.

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.

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.

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

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

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, 439-457, 1999.

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.

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, 110-130, 2010.

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.

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

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.

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.

Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman’s Textbook of
Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6 th ed., pp.320-349, 2006.

Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman’s Textbook of
Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6 th ed., pp.320-349, 2006.

Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman’s Textbook of
Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6 th ed., pp.320-349, 2006.

Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman’s Textbook of
Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6 th ed., pp.320-349, 2006.

Monteiro-Riviere NA. Ultrastructural Evaluation of the Porcine Integument. In Swine in
Biomedical Research, Tumbleson ME (ed), NY, Plenum Press, vol 1.pp 641-655, 1986.

Monteiro-Riviere NA: Integument. In Eurell J, Frappier B, eds. Dellman’s Textbook
of Veterinary Histology, Blackwell Publishing, Ames, Iowa, 6 th ed., pp.320-349, 2006

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.