Cutaneous biotransformation

Cutaneous biotransformation is mostly associated with the stratum basale layer where there can be phase I and phase II metabolism. However, the skin is not very efficient, compared to the liver. The epidermal layer accounts for the major portion of biochemical transformations in skin, although the total skin activity is low (2-6% that of the liver). Where activity is based on epidermis alone, that layer is as active as the liver or, in the case of certain toxicants, several times more active. For some chemicals, metabolism can influence absorption, and transdermal delivery systems of drugs utilize this activity. For example prodrug such as lipid esters are applied topically, and cutaneous esterases liberate the free drug. These basal cells and extracellular esterases have been shown to be involved in detoxification of several pesticides and bioactivation of carcinogens such as benzo(a)pyrene. For rapidly penetrating substances, metabolism by the skin is not presently considered to be of major significance, but skin may have an important first-pass metabolic function, especially for compounds that are absorbed slowly. 

Subcellular localization studies have identified P-450-dependent monooxygenase activity in adult hairless mice sebaceous glands. Phase II conjugation pathways have also been identified in skin. Extracellular enzymes including esterases are present in skin, which has been utilized to formulate lipid-soluble ester prodrugs which penetrate the stratum corneum and then are cleaved to release active drug into the systemic circulation. Finally, co-administration of enzyme inducers and inhibitors modulate cutaneous biotransformation and thus alter the systemic toxicity profile. These metabolic interactions that occur in skin have attracted a great deal of research attention and clearly illustrate that skin is more than a passive barrier to toxin absorption. 

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... 

Qiao. G. L., and Riviere, J. E, (1995). Significant effects of application site and occlusion on the pharmacokinetics of cutaneous penetration and biotransformation of paraihion in vivo in swine. J. Pharm. Sci. 84,423-432. 

There have been three types of studies conducted in the IPPSF toxicology, percutaneous absorption (including biotransformation and pharmacokinetic modeling), and cutaneous drug distribution (drug administered by intraarterial infusion). The first two are discussed in this chapter. 

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