Food-induced changes in absorption from two controlled-release formulations of theophylline (Uniphyl tablets [Purdue Frederick Co.] and Theo-Dur Sprinkle [Key Pharmaceuticals, Inc.]) were studied in healthy male nonsmokers. Although the two forms exhibited a theophylline in vitro dissolution rate that was independent of changes in pH from 1 to 8, they showed substantial but opposite food-induced absorption changes. In a 12-subject, three-way, single-dose, randomized, crossover study the bioavailability of theophylline relative to immediate-release aminophylline tablets increased from 53% +/- 23% (means +/- SD) to 96% +/- 46% when Uniphyl (two 400 mg tablets) was taken under fasting and nonfasting (high fat content meal) conditions, respectively. On the other hand, in a separate six-subject, two-way, randomized, crossover study, food reduced the bioavailability of theophylline from Theo-Dur Sprinkle: Theophylline bioavailability in the nonfasting state was only 53% +/- 9% that in the fasting state.

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Azidothymidine (AZT) was used as a model drug to study the effect of iontophoresis on the skin permeation of a neutral compound. The rate of in vitro permeation across hairless rat skin was low and highly variable. With iontophoresis treatment the permeation rate was two- to threefold greater than by passive diffusion. The addition of varying amounts of sodium chloride to the donor enhanced the iontophoretic permeation rate an additional two- to threefold possibly due to convective forces. The addition of N-decylmethyl sulfoxide (C10MSO) to the donor increased the permeation rate by several hundred-fold over passive diffusion for hairless rat skin and approximately 75-fold for human skin. No additional enhancement was observed with the combination of C10MSO and iontophoresis treatment at constant current or constant voltage. It may be that the presence of C10MSO lowers the zeta potential of the skin, thus enhancement due to convective flow is minimized.

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.