Percutaneous Absorption and Penetration

The tendency for a toxicant to traverse the skin is a primary determinant of its der-matotoxic potential. That is, a chemical must penetrate the stratum comeum in order to exert toxicity in lower cell layers. The quantitative prediction of the rate and extent of percutaneous penetration (into skin) and absorption (through skin) of topically applied toxicants is complicated by the biological complexity discussed above. 

The stratum corneum has been estimated to contribute 1000 times the diffusional resistance to chemical penetration as the layers beneath it, except for extremely lipid-soluble compounds with tissue/water partition coefficients greater than 400. As in most other epithelial tissues, the two other layers of the skin (dermis and subcutaneous tissue) offer little resistance to penetration. Once a substance has penetrated the outer epithelium, these tissues are rapidly traversed. This may not be true for highly lipid-soluble compounds, because the dermis may function as an additional aqueous barrier preventing a chemical that has penetrated the epidermis from being absorbed into the blood. 

The rate of diffusion of a topically applied toxicant across the rate-limiting stratum corneum is directly proportional to the concentration gradient across the membrane, the lipid/water partition coefficient of the drug, and the diffusion coefficient for the compound being studied. This can be summarized by Fick s law of diffusion in the equation 

In dermatotoxicology, the amount of toxicant per area of skin (e.g., mg/cm2), rather than the amount of toxicant per unit of body weight (e.g., mg/kg), used in oral and parenteral studies is the primary determinant of dose. This explains why infants, with a relatively small ratio of skin surface area to body mass, are particularly prone to systemic toxicity from topical poisons when large areas of skin are exposed. This is further potentiated in neonates, who do not have a fully developed cutaneous barrier. 

Occlusion of the skin, seen with application of water-impermeable drug vehicles or patches, alters the rate and extent of toxicant absorption. As the skin hydrates, a threshold is reached where transdermal flux dramatically increases (approximately 80% relative humidity). When the skin becomes fully hydrated under occlusive conditions, flux can be dramatically increased. This occlusive effect must be accounted for when extrapolating toxicology studies conducted under occlusive conditions to field scenarios where the ambient environmental conditions are present. Hydration may also markedly affect the pH of the skin, which varies between 4.2 and 7.3. Therefore, dose alone is often not a sufficient metric to describe topical doses when the method of application and surface area become controlling factors. Dose must be expressed as mg/cm2 of exposed skin. 

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One in vivo Study on pigs (Qiao et al.. 1997) demonstrated that occlusion significantly enhanced pen-tachlorophcnol (PCP) absorption in a soil-based mixture from 29 to 85% of dose and changed the shape of the absorption profile in blood and plasma. The study also suggested that occlusion enhanced metabolism of PCP and resultantly the partitioning between plasma and red blood cells. Occlusion was kinctically linked to modification of cutaneous biotransformation of topical parathion (Qiao and Riviere, 1995). Occlusion enhanced cutaneous metabolism of parathion to paraoxon and to p-nitrophenol as well as the percutaneous absorption and penetration of both parathion and p-nitrophenol, This probably resulted in the... 

Riviere et al. (1999) used the isolated perfused porcine skin flap model to study absorption and disposition of JP-8. The percutaneous absorption and cutaneous disposition of topically applied neat Jet-A and JP-8 jet fuels were assessed by monitoring the absorptive flux of the marker components 14C naphthalene and 3H dodecane simultaneously. Absorption of 14C hexadecane was estimated from JP-8. Data were not reported in absolute amounts or concentrations. Instead, the objectives were to determine the relative absorption of the individual marker components from jet fuel, and the effect of a specific jet fuel s composition on the absorption of a specific marker. Having evaluated the absorption of only three of the 228 major nonadditive hydrocarbon constituents of the fuels, the authors stated that this is insufficient information to conduct risk assessments on jet fuels. However, the authors conclusions are informative. Naphthalene penetrated the skin more rapidly than dodecane or hexadecane, but the latter compounds had a larger fraction of the dose deposited in the skin. There were also differences in naphthalene and dodecane absorption and skin deposition between the fuels. These findings reinforce the difficulty of predicting risk for complex mixtures such as jet fuels. 

There are three basic steps in the process of percutaneous absorption, and the first two are governed by the physicochemical properties of the permeating molecule. Initially the permeant has to escape from the vehicle and penetrate into the stratum corneum (step 1), which is largely a function of partition and solubility characteristics. Diffusion across the stratum... 

Scheuplein, R. J., and I. H. Blank. 1973. Mechanism of percutaneous absorption. IV. Penetration of nonelectrolytes (alcohols) from aqueous solutions and lfompure liquids./. Invest. Dermatol. 60 286-296. 

Most studies on percutaneous absorption emphasize the penetration of drugs, toxins, and other solutes into and through the skin as described in this book. Percutaneous absorption is also dependent on the clearance of solutes from the skin and transport into deeper layers of the skin (Figure 13.1). Clearance mechanisms in the avascular viable epidermis, diffusion in the dermis, and export from/within the dermis include solute diffusion and physiological transport by the dermal blood and lymphatic systems. This chapter focuses on the nature of these clearance mechanisms and how they affect the rates of percutaneous absorption and the levels of solute in skin and tissue. We consider first the role of blood flow, followed by the role of binding, transport to deeper tissues, and then the role of lymphatics. 

Li et al. (2001) investigated the effects of eucalyptus oil on percutaneous penetration and absorption of a clobetasol propionate cream using vertical diffusion cells. The in vitro penetration of the cream containing 0.05% clobetasol propionate through mouse abdominal skin was detected at 2,4,6, 8, 10, and 24 h (cumulative amount Q, pg/g) and at steady state (/, pg/cm /h). The quantity of clobetasol propionate within the whole stria of skin after 24 h (D, pg/g) was measured too. Eucalyptus oil was able to increase Q and J, whereas D was not influenced in that way, which indicates that eucalyptus oil would increase clobetasol propionate percutaneous absorption and cause unwanted side effects. 

Alcohol and alcohol ether sulfates have also been studied to determine their toxicity by percutaneous absorption in rats and guinea pigs [354-356]. Alcohol ether sulfates penetrate in the order of 1 ng/cm2/day and alcohol sulfates are less penetrant by a factor of 10. The surfactant absorbed was metabolized. Since it is known that human skin is less permeable than animal skin, only very small amounts of alcohol or alcohol ether sulfates can be absorbed even in the case of complete body exposure. 

The capacity of the photoactive material to penetrate into normal skin by percutaneous absorption as well as into skin altered by trauma, such as maceration, irritation, and sunburn. 

Scheuplein, R.J. (1965). Mechanism of percutaneous absorption, (i) Routes of penetration and the influence of solubility. J. Invest. Derm. 45 334-346. 

Hydrogen cyanide is moderately lipid-soluble, which, along with its small size, allows it to rapidly cross mucous membranes, to be taken up instantly after inhalation, and to penetrate the epidermis. In addition, some cyanide compounds, such as potassium cyanide, have a corrosive effect on the skin that can increase the rate of percutaneous absorption (NIOSH 1976). Information regarding dermal absorption in animals and evidence that cyanide can be absorbed through the skin of humans is provided in Sections 2.3.1.3 and 2.2.3, respectively. 

Percutaneous absorption is another route of interest for the administration of peptides [158], with metabolism being a complicating factor [159]. Thus, [Leu5]enkephalin and Tyr-Pro-Leu-Gly-NH2 were rapidly degraded on the dermal side after penetration through rat skin preparations [160]. The use of inhibitors confirmed the involvement of serine proteases and metalloenzymes. 

Experimental studies on the percutaneous absorption of hydrocortisone fail to reveal a significant increase in absorption when applied on a repetitive basis and a single daily application may be effective in most conditions. Ointment bases tend to give better activity to the corticosteroid than do cream or lotion vehicles. Increasing the concentration of a corticosteroid increases the penetration but not proportionately. For example, approximately 1% of a 0.25% hydrocortisone solution is absorbed from the forearm. A 10-fold increase in concentration causes only a fourfold increase in absorption. Solubility of the corticosteroid in the vehicle is a significant determinant of the percutaneous absorption of a topical steroid. Marked increases in efficacy are noted when optimized vehicles are used, as demonstrated by newer formulations of betamethasone dipropionate and diflorasone diacetate. 

Bucks, D., and H.I. Maibach. 1999. Occlusion does not uniformly enhance penetration in vivo. In Percutaneous absorption Drugs, cosmetics, mechanisms, and methodology, 3rd ed., eds. R.L. Bro-naugh and H.I. Maibach. New York Marcel Dekker, chap. 4. 

In this section, we outline the applications of IR microscopic imaging to the molecular level determination of dermal and transdermal percutaneous absorption. The rationale for these experiments is that drugs often exhibit low penetration rates... 

Absorption through the skin, percutaneous absorption, is an important mechanism by which xenobiotic substances can enter the body. The surface stratum corneum layer is the main barrier to such absorption, and when it is shed or compromised, skin is much more susceptible to penetration by xenobiotic substances. A test for the ability of a hydrophobic xenobiotic substance to penetrate skin is to measure the partitioning of such a substance between water and powdered stratum corneum cells. 

This chapter is not an exhaustive list of all chemicals with skin-penetrating abilities. Consequently, any exclusion of a chemical from this list does not necessarily imply an inability for percutaneous absorption. When in doubt, the user should check the chemical label, material safety data sheet, manufacture date, and other details to achieve chemical safety (Table 16-1). 

Schaefer, H. and Redelmeier, T.E. (eds) (1996) Skin barrier. Principles of percutaneous absorption. Karger AG, Basel. Cleary, G.W. (1993) Transdermal Delivery Systems A Medical Rationale. In Topical Drug Bioavailability, Bioequivalence, and Penetration. (Shah, V.P. and Maibach, H.I., eds). Plenum Press, New York, pp. 17-68. 

There is clear relationship between the mass of a chemical residing in the stratum comeum that has been washed 30 min after application and the eventual penetration that can be measured in urine and/or blood. This principle has led to a facile method for estimating percutaneous absorption in animals and man. One samples and measures stratum comeum content with cellophane tape sampling. This method... 

Loss of radioactive material from the skin surface has been used to estimate in vivo percutaneous absorption. The difference in applied dose and residue on the skin is assumed to be absorbed. The characteristics of the radioisotope, penetrant, and vehicle may limit the usefulness of this procedure. Volatile materials may leave the surface without penetrating, and it is difficult to recover all material from the skin surface. In addition, skin may retain a reservoir of the penetrant that has not entered the circulation. 

In order to have a basic understanding and appreciation of how chemicals may interact with skin, its anatomy, physiology, and chemical composition must be fully grasped. All of the aforementioned biological functions and structural adaptations have a substantial impact on the skin s barrier properties and the rate and extent of percutaneous absorption. When a compound or toxicant is applied topically, it must penetrate through several cell layers of the skin in order to be absorbed by the capillaries for systemic distribution. Alternatively, it may have a direct effect on the keratinocytes themselves. Skin can be anatomically divided into two principal components, the outermost epidermis and the underlying dermis. 

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