ON THE NON-GAUSSIAN DISTRIBUTION OF HUMAN SKIN PERMEABILITIES

Human skin demonstrates considerable inter- and intra-donor variability to transdermal drug permeation. In the past, for a given permeant, replicate measurements of diffusional parameters have been (at least tacitly) assumed to provide a normal distribution with a wide degree of dispersion. We have monitored the permeability of human abdominal skin in vitro to model hydrophilic (5-fluorouracil, 5-FU) and lipophilic (oestradiol, ES) drugs. Drug permeation from a saturated aqueous solution was assessed using stainless-steel diffusion cells with an aqueous flow-through receptor solution. Diffusion was characterised by evaluation of drug permeability coefficients at steady-state flux. The variability of drug permeability coefficients for 644 determinations of 5-FU from 71 skin specimens and 221 replicates of ES from 28 specimens did not follow a normal distribution. Our data show that permeability coefficients for both drugs followed more closely log-normal distributions. Additionally, our results indicate that the specimen population of cadavers may be comprised of two subgroups; those with higher than expected permeability, and the majority providing 'ordinary' permeability. No relationship was evident between specimen age, sex or storage time and drug permeability coefficient. When data are found to be log-normally distributed the appropriate measure of central tendency is the geometric mean, since the arithmetic mean tends to be artificially increased because of the nature and degree of a skewed distribution.