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Applying a xenobiotic to the skin to treat a systemic medical condition is not new. Ointments and other salves have been applied topically for thousands of years for the treatment of local and systemic diseases. During World War I, dynamite workers used nitroglycerin applied to their hatbands to prevent angina when they were away from work and no longer exposed to organic nitrates.36 Mustard seed plaster for chest congestion, releasing allyl isothiocyanate, and topical elemental mercurials for syphilis are other examples of such use in the beginning of the 20th century.28 Over the past 30 years, an increasing number of medications have been formulated in transdermal delivery systems, or patches, to allow for systemic delivery of a xenobiotic. The first commercially available patch delivered scopolamine for motion sickness (1979), which was followed by nitroglycerin for chronic angina (1981) and then fentanyl for chronic pain management (1990). In the United States, the nicotine patch remains the most widely used transdermal patch, because of both the significant need for smoking cessation and its nonprescription availability. Certain medicinal xenobiotics, such as testosterone, can be administered without a patch, as a spray or gel.22 Further, xenobiotics are absorbed transdermally, as occurs with nicotine following direct exposure to moist tobacco leaf in patients with “green tobacco sickness” or following direct contact with organic phosphorus compound spraying.3

The skin is the largest organ in the body, although it is not widely used as a route for intentional xenobiotic delivery. However, there are several benefits of transdermal delivery of xenobiotics. This route provides a noninvasive means to discretely administer xenobiotics. Patches result in steady plasma concentrations that reduce side effects, particularly for xenobiotics with short half-lives. Although metabolism occurs in the skin, metabolism does not appear to be highly consequential for the majority of currently used transdermal xenobiotics.18 The patches are designed to be left in place for long periods of time, which improves compliance. Importantly, the avoidance of first-pass metabolism permits an effective means of delivery for poorly orally bioavailable xenobiotics. However, because absorption through the skin following simple application is passive, there is a large degree of variability among both patients and xenobiotics. Newer nanocarriers and minimally invasive technologies, as discussed below, attempt to overcome this limitation.11,16

This chapter does not cover xenobiotics applied to the skin to produce an effect locally. These xenobiotics are available in patch formulation (eg, lidocaine and capsaicin) or as a directly applied preparation, such as a variety of antibiotics or acne creams (eg, tretinoin). Locally acting formulations (eg, lidocaine) typically provide only trivial amounts of systemic xenobiotic;6 for example, with tretinoin, despite devastating fetal complications when taken orally, these same effects do not occur when applied topically.20 Some xenobiotics, such as capsaicin, have both local (for postherpetic neuralgia) and systemic (for cannabinoid hyperemesis syndrome) effects.7,31

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