METABOLISM, DISTRIBUTION, AND TRANSDERMAL PERMEATION OF A SOFT CORTICOSTEROID, LOTEPREDNOL ETABONATE

The soft corticosteroid, loteprednol etabonate (chloromethyl 17alpha-ethoxycarbonyloxy-11beta-hydroxy-3-oxoandrosta-1,4-diene-17beta-carboxylate), I, was designed based on the "inactive metabolite approach." Accordingly, I should be metabolized by hydrolysis to the corresponding inactive cortienic acid derivative, II. The in vitro and in vivo metabolism of I indeed yielded mainly this inactive metabolite, which is more hydrophilic and thus readily eliminated from the body. Relatively high levels of I were found in tissues after intravenous administration of the drug in rats. The permeability of I through hairless mouse skin was comparable to what has been found for related "hard" steroids, without significant metabolism taking place in the skin.