Bioavailability of topically administered steroids: A "mass balance" technique

The percutaneous absorption of four steroids (hydrocortisone, estradiol, testosterone, and progesterone) has been measured in vivo in man under occluded and "protected" (i.e., covered, but non-occlusive) conditions. The experimental approach, involving simple modifications of standard radiochemical methodology, has enabled excellent "mass balance" and dose accountability to be achieved. Consequently, the utility of the procedure for the measurement of in vivo topical bioavailability can be inferred. In addition, because of the precision and accountability of the results, the technique offers a potential means to establish quantitative structure-penetration relationships for skin absorption in man. It was found that steroid absorption increased with increasing lipophilicity up to a point, but that penetration of progesterone (the most hydophobic analog studied) did not continue the trend and was at least partly rate-limited by slow interfacial transport at the stratum corneum-viable epidermis boundary. Comparison of data obtained from the occluded and "protected" experiments permitted the effect of occlusion (defined as the complete impairment of passive transepidermal water loss at the application site) to be assessed. Occlusion significantly increased percutaneous absorption of estradiol, testosterone, and progesterone but did not effect the penetration of hydrocortisone. A mechanism is proposed to explain why the absorption of the more lipophilic steroids is enhanced by occlusion but that of the most water-soluble (i.e., hydrocortisone) is not. It is suggested that the rate-determining role of the sequential steps involved in percutaneous absorption can be revealed by experiments of the type described using related series of homologous or analogous chemicals.