Charles Eckhart

Relationship among physicochemical properties, skin permeability, and topical activity of the racemic compound and pure enantiomers of a new antifungal

The topical antifungal Sch-39304 is a racemic compound comprised of two enantiomers, Sch-42427 and Sch-42426, only one of which (Sch-42427) is pharmacologically active. The pure enantiomers have a lower melting point and, therefore, a higher solubility than the racemic compound. Because of these differences in physicochemical properties, the concentration of the pure enantiomers in vehicles and in the skin was predicted to be an order of magnitude higher than the racemic compound. It was hoped that the pharmacological activity would also be higher. By measuring the flux of the chiral forms through human cadaver skin, the expected differences in skin solubility were confirmed. However, only a minimal difference between racemate and active enantiomer was observed in the lesion scores using a guinea pig dermatophyte model. By fitting the data to the Emax pharmacodynamic model, it is demonstrated that the maximum effect occurs at a concentration lower than the saturated concentration of the less soluble racemic compound. The data illustrate that the efficacy of topically active compounds may not be linearly related to drug concentration in either the vehicle or the skin.