The effects of Δ1-cortienic acid on skin blanching, pharmacokinetics and stability of loteprednol etabonate

The effect of Δ1-cortienic acid (Δ1-CA) on human skin blanching activity of the soft corticosteroid, loteprednol etabonate (LE), has been studied. Ten volunteers had applied to their forearms a dose of LE ranging from 0.1 to 1 mM, or LE from 0.1 to 1 mM in combination with 2-times the concentration of Δ1-CA ( 0.2 – 2 mM). The results indicate that Δ1-CA increased LE's effect on human vasoconstriction/skin blanching activity, both in the intensity and duration. This enhancing effect of Δ1-CA was also observed in other blanching studies with other corticosteroids, such as hydrocortisone. The enhancement may occur through the displacement of LE bound to transcortin (also known as corticosteroid-binding globulin, or CBG) by Δ1-CA as Δ1-CA has a higher affinity for CBG than that for glucocorticoid receptor (GR), resulting in more free-LE to act on GR, and increased skin blanching. In rat studies, intravenous injection of Δ1-CA (5–50 mg/kg) did not affect the pharmacokinetics of LE (5 mg/kg), indicating that Δ1-CA is safe for combined use with LE. In stability studies, the presence of Δ1-CA at the same concentrations as LE in aqueous suspension (0.1 and 0.2%) significantly increased the stability of LE. Thus, the combination of 1-CA with LE serves an enhancing and stabilizing role while not impacting the pharmacokinetic properties of LE.