Skin Absorption Pathways

Skin absorption pathways can be divided into the transport (a) across the intact stratum corneum and (b) along using skin appendages. The physicochemical properties of the compound, as well as the used formulation, are the main factors influencing the choice of pathway. 

Generally, the stratum corneum is considered to be the rate limiting layer of the skin with regard to transdermal drug absorption. However, for the invasion of very lipophilic compounds, the bottleneck moves from the stratum corneum down to the viable, very hydrophilic layer of the epidermis, due to substances reduced solubility in this rather aqueous layer [14], 

Originating from the structure of the stratum corneum, two permeation pathways are possible (a) the intercellular route and (b) the transcellular route. 

The intercellular route is considered to be the predominantly used pathway in most cases, especially when steady-state conditions in the stratum corneum are reached. In case of intercellular absorption, substance transport occurs in the bilayer-structured, continuous, intercellular lipid domain within the stratum corneum. Although this pathway is very tortuous and therefore much longer in distance than the overall thickness of the stratum corneum, the intercellular route is considered to yield much faster absorption due to the high diffusion coefficient of most drugs within the lipid bilayer. Resulting from the bilayer structure, the intercellular pathway provides hydrophilic and lipophilic regions, allowing more hydrophilic substances to use the hydrophilic and more lipophilic substances to use the lipophilic route. In addition, it is possible to influence this pathway by certain excipients in the formulation. 

Under normal conditions, the transcellular route is not considered as the preferred way of dermal invasion, the reason being the very low permeability through the corneocytes and the obligation to partition several times from the more hydrophilic corneocytes into the lipid intercellular layers in the stratum corneum and vice versa. The transcellular pathway can gain in importance when a penetration enhancer is used, for example, urea, which increases the permeability of the corneocytes by altering the keratin structure. 

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In this study, 4.4 mg of lead equivalent was applied to the skin under a covered wax/plastic patch on the forearms of human subjects of the applied dose, 1.3 mg of lead was not recovered from skin washings. The amount that actually remained in (or on) the skin and the mass balance of the fate of this lead was not determined it may have been absorbed or eliminated from the skin by exfoliation of epidermal cells. Thus, while this study provides evidence for dermal absorption of lead, it did not quantity the fraction of applied dose that was absorbed. The quantitative significance of the dermal absorption pathway as a contributor to lead body burden remains an uncertainty. The wax/plastic patch provided a means by which the lead compounds could permeate or adhere to the skin. The effect of concentration in aqueous solution may cause skin abrasion through enhanced acidity since the lead ion is acidic. Abraded skin is known to promote subsequent higher lead penetration. 

In animal studies [9], up to 8% of isotopically labelled mercuric chloride applied to the skin was absorbed within 5 h. The state of the skin is one factor which determines the rate of absorption [10]. Passive diffusion cannot be the only process involved, since the absolute absorption rate of mercury increases with increasing concentration up to a plateau value. In addition, skin absorption probably occurs transepidermally rather than via the follicular pathway [11]. 

In recent years, several types of in vitro approaches have been developed to assess the absorption and metabolic pathways of substances. Except for the OECD TG 428, Skin Absorption In Vitro Method, none of these test methods have yet been adopted as a test guideline method. 

Absorption of styrene by inhalation is the major path of absorption into the body. Skin absorption of the liquid is also significant. According to an estimate, contact with styrene-saturated water for an hour or brief contact with the liquid may result in absorption equivalent to 8 hours of inhalation of 12 ppm (Dutkiewicz and Tyras 1968). It may accumulate in the body due to its high solubility in fat. This would happen when the metabolic pathway becomes saturated at exposure concentrations of 200 ppm (ACGIH... 

The effects of land contamination are widespread and past industrial activity is the most significant factor. Soil transport and reaction processes are relatively slow compared to air and water, so contamination tends to persist at the point of deposition for a long period. Table 9.5 summarizes common hazards and examples of contaminants. These contaminants can affect humans by absorption into the body through oral, inhalation or skin adsorption pathways. For volatile compounds and dusts, inhalation is the most important pathway. This is of particular concern with young children playing on contaminated land. The re-use of derelict, industrial sites has emphasized many of these problems . 

There arc four pathways for substances to enter the body —Absorption through contact with the skin and eyes —Inhalation —Ingestion —Injection/puncture... 

Much of the attention focused on e.xposure assessment has come recently. This is because many of the risk assessments done in tlie past used too many conseix ative assumptions, wliich caused an ovcrcstimation of the actual exposure. Without exposures there are no risks. To experience adverse effects, one must first come into contact with the toxic agent(s). Exposures to chemicals can be via inlialation of air (brcatliing), ingestion of water and food (eating and drinking), or absorption Uu ough the skin. These arc all pathways to the human body. 

Studies undertaken specifically to evaluate absorption of either 1,3-DNB or 1,3,5-TNB in humans after an inhalation exposure were not located. However, a study of an occupational exposure to 1,3-DNB showed that workers developed cyanosis within the first 24 hours after exposure (Okubo and Shigeta 1982). Inhalation was considered the major exposure pathway since skin contact was with 1,3-DNB in solid form. There was no information, however, on the amount of 1,3-DNB present in the air or on the amount of particulate 1,3-DNB deposited on the workers skin. 

Mechanism of Action Modulates differentiation and proliferation of epithelial tissue, binds selectively to retinoic acid receptors. TherapeutkEffect Restores normal differentiation of the epidermis and promotes reduction of epidermal inflammation. Pharmacokinetics Minimal systemic absorption occurs through the skin. Binding to plasma proteins is greater than 99%. Metabolism is in the skin and liver. Elimination occurs through the fecal and renal pathways. Half-life 18 hr. 

The pharmacokinetics and metabolism of tazarotene (2) is especially worth noting. Topical gel application provides the direct delivery of tazarotene into the skin. Ten hours after a topical application of 0.1% tazarotene gel to the skin, approximately 4-6% of the dose resides in the stratum comeum and 2% of the dose is distributed to the viable epidermis and dermis. As depicted in Scheme 3, both tazarotene (2) and tazarotenic acid (11) undergo further metabolism to their corresponding sulfoxides 12 and 13, respectively. Sulfoxides 12 and 13, in turn, are even further oxidized to sulfones 14 and 15, respectively. These very polar metabolites do not accumulate in adipose tissue, but are rapidly eliminated via both urinary and fecal pathways with a terminal half-life of approximately 18 h. A lesson learned here is that installation of a sulfide moiety promotes clearance because it is oxidized to polar metabolites that are rapidly cleared. As the consequence, the systemic exposure is minimized. Percutaneous absorption of tazarotene (2) led to a plasma concentration below 1 gg/L. The systemic... 

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