PERCUTANEOUS ABSORPTION OF ADRENAL STEROIDS 151 cordsone acetate solutions these workers reported that the potency ratio for inducing thymus involution for cortisone:hydrocortisone was 1.0:3.4. Malkinson, ez al. (29), investigated the percutaneous absorption of cord- sone-4-C TM acetate after application of steroid ointment to normal skin sites in three volunteers. The experimental technique used was similar to that already described for hydrocortisone-4-C TM. Penetration of the hormone was demonstrated by detection of radioactivity in the 17-ketosteroid frac- tion of twenty-four-hour urine specimens. Cordsone excretion reached a peak in the first twenty-four hours (in contrast to an excretion peak in the second twenty-four hours for hydrocortisone (15), but lower levels of radioactivity persisted in the urine throughout the six- to seven-day period during which cordsone ointment remained on the skin surface. As was the case for hydrocortisone, it was estimated that the quantitative absorp- tion of cordsone through normal human skin sites was less than 1 per- cent. In later studies using the gas-flow cell to measure residual levels of radio- activity locally, it was observed that after application of cortisone-4-C TM acetate to stripped human skin sites there was no appreciable increase in penetration of the steroid (21). Even allowing for the small error inherent in the method used this finding contrasted markedly with the previous observations of almost complete absorption of hydrocortisone-4-C TM free alcohol from stripped skin areas within four to six hours (21). Whether solubility differences between the acetate and the free compound account for these findings or whether cordsone enters. the skin only through the pilosebaceous apparatus has not yet, been determined. Possible explanations for the differences in therapeutic response following the topical use of cordsone and hydrocortisone will be considered later. 9-(•-FLUOROHYDROCORTISONE The initial introduction of 9-•-fiuorohydrocortisone for topical use was enthusiastically received when studies revealed that the anti-inflammatory potency of this compound was far greater than that of hydrocortisone. Concentrations of 0.1 to 0.25 per cent fiuorohydrocortisone compared favorably in topical therapeutic effectiveness with 1.0 to 2.5 per cent hydro- cordsone preparations (30-32). Because of the potent sodium-retaining effects of fiuorohydrocortisone (33), however, clinical evidence for the per- cutaneous absorption of this compound was soon forthcoming. It should be emphasized, moreover, that to the present time fluorohydrocortisone is the only clinically used adrenal steroid analog known to be capable of eliciting systemic changes following the use of topical preparations. Fitzpatrick, et aL (14) reported five instances of increased weight and ankle edema in patients using 0.2 per cent fluorohydrocortisone acetate lotion for the treatment of eczematous dermatoses. The smallest total

152 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS dosage of hormone applied by any of these patients was 30.0 mgm. within a twenty-four-hour period. In some cases the edema and weight gain sub- sided with continued therapy as the dermatitis improved. Further study of seven patients showed that urinary sodium excretion was reduced in the first two or three days of local treatment, and in three individuals urine output was markedly diminished (14). Following this initial period and despite the continued applications of fluorohydrocortisone lotion, there was a subsequent rise in urinary sodium excretion coincident with improvement in the dermatitis. Livingood, et aL (34), also found edema, weight gain, and/or diminished urinary excretion of sodium in a group of eleven patients receiving topical fiuorohydrocortisone. In one of two normal subjects studied similar changes were seen after application of steroid lotion to the anogenital region. In regard to the last observation, absorption of most compounds may be greater through mucous membrane surfaces than through normal skin sites. This fact was well demonstrated for adrenal steroids by the prior study of Liddle with hydrocortisone (19). Although the percutaneous ab- sorption of fiuorohydrocortisone through eczematous skin sites and normal mucous membrane surfaces has been well established, no definitive demon- stration of penetration through normal human skin sites has been reported. Fluorohydrocortisone is almost certainly absorbed in small quantities through normal skin, but the observations of weight loss, subsidence of edema, and increased urinary sodium excretion in patients responding to continued treatment with fiuorohydrocortisone (14) indicate that the com- pound passes far more readily through the damaged barrier of inflammatory skin sites than through normal epidermis. A • HYDROOORTISONE ANALOGS To date studies on the percutaneous absorption of the A • derivatives of cortisone and hydrocortisone have not been reported. From the experience gained with the older compounds it might be anticipated that small amounts of the newer steroids are absorbed from normal skin sites, but direct meas- urements of absorption will be possible only with the use of radioisotope labeled compounds. Recently 6-methylprednisolone, labeled with C TM in the 6-a-methyl group, and triamcinolone acetonide, labeled with 0 4 in the acetone grouping, have become available for investigative purposes. Although initial studies of percutaneous absorption through normal and stripped skin sites have been carried out with both compounds in our labora- tories, the significance of the accumulated data cannot yet be assessed. The labeling of these hormones outside of the steroid nucleus (which re- mains metabolically intact) raises the possibility of enzymatic splitting of the radioisotope labeled radicals from the parent indecule. Investigations