Diffusion of [2-14C]Diazepam Across Hairless Mouse Skin and Human Skin

Abstract

The objectives of this study were to investigate the absorption of diazepam applied topically to the hairless mouse in vivo and to determine the diffusion of diazepam across isolated hairless mouse skin and human skin. [14C]Diazepam was readily absorbed after topical administration to the intact hairless mouse, a total of 75.8% of the 14C-label applied being recovered in urine and feces. Diazepam was found to diffuse across human and hairless mouse skin unchanged in experiments with twin-chambered diffusion cells. The variation in diffusion rate or the flux for both human and mouse tissues was greater among specimens than between duplicate or triplicate trials for a single specimen. Fluxes for mouse skin (stratum corneum, epidermis, and dermis) were greater than for human skin (stratum corneum and epidermis): 0.35-0.61 microgram/cm2/h for mouse skin vs 0.24-0.42 microgram/cm2/h for human skin. The permeability coefficients for mouse skin ranged from 1.4-2.4 X 10(-2)cm/h compared with 0.8-1.4 X 10(-2)cm/h for human skin. Although human stratum corneum is almost twice the thickness of that of the hairless mouse, the diffusion coefficients for human skin were 3-12 times greater (0.76-3.31 X 10(-6) cm2/h for human skin vs 0.12-0.27 X 10(-6) cm2/h for hairless mouse) because of a shorter lag time for diffusion across human skin. These differences between the diffusion coefficients and diffusion rates (or permeability coefficients) suggest that the presence of the dermis may present some barrier properties. In vitro the dermis may require complete saturation before the diazepam can be detected in the receiving chamber. [14C]Diazepam was not detected in the receiving chamber of the Franz cell apparatus in experiments with human skin. This indicated that the rate of diffusion was less than 0.09 microgram/cm2/h. Since this diffusion technique more closely resembles topical administration to humans, these results appear to indicate that achieving therapeutic concentrations in humans may be difficult. In addition, the hairless mouse may not be a suitable model for predicting percutaneous absorption of diazepam in humans.