Rp

Retinol w.

Day 1

Retinol

□ Stratum corneum I Epidermis

Day 1

Day 3 Day 6 Day 11 Day 18 Time after treatment

FIGURE 5. The levels of retinyl palmitate (ng/mg tissue) (Panel A) and retinol (Panel B) in stratum corneum, epidermis, and dermis of female SKH-1 mice topically treated with 0.5% retinyl palmitate cream for 4 consecutive days and sacrificed 1,3,6,11, and 18 days after last retinyl palmitate cream application.

the last application of retinyl palmitate (Yan et al., 2006a). Since the level of retinol in the skin of the mice treated with retinyl palmitate is significantly higher than that in the control animals, these results clearly indicate that retinyl palmitate was metabolized into retinol in the skin. These results demonstrate that elevated levels of both retinyl palmitate and retinol persist in skin after repeated topical treatment with retinyl palmitate. The biological consequence of persistently elevated levels of these retinoids is unclear at this time.

The results of these clinical and experimental studies uniformly demonstrate that topical application is an effective strategy for loading the skin

FIGURE 6. The total levels of retinyl palmitate (Panel A) and retinol (Panel B) in the whole skin of female SKH-1 mice topically treated with 0.5% retinyl palmitate cream for 4 consecutive days and sacrificed 1, 3, 6, 11, and 18 days after last retinyl palmitate cream application.

with substantial levels of vitamin A. In addition, these studies indicate that topically applied retinol and retinyl palmitate trigger biochemical changes in the skin that might be expected from perturbation of previously established retinoid homeostasis. These biochemical changes include increased expression of retinol and retinoic acid-binding proteins as well as increased levels of enzymes that metabolize retinoic acid.

Concerns have been raised about potential systemic toxicity resulting from the increased use of retinol and retinyl esters in topically applied products. Clinical studies have been reported that address this issue. Ries and Hess (1999) have reported that topical application of retinol at concentrations expected in some cosmetics (0.25%) causes no increase in plasma levels of retinol or its metabolites; however, details of topical exposure and methods of analysis were not provided. Nohynek et al. (2005) have published results from a clinical study involving 2 groups of 14 female volunteers. Prior to initiating topical applications, baseline plasma levels of retinol, retinyl esters, and acids were determined. Thereafter, one group of subjects received daily application (~1 mg/cm2, over 3000 cm2 of the back, hips, and legs) of a cream containing 0.34% retinol, while the other group received daily application of a cream containing 0.55% retinyl palmitate. Topical applications continued for 3 weeks. Plasma levels of retinoid were determined on the first and the last day of topical treatments. On each day designated for sampling plasma, multiple samples were drawn over a 24-h period to compensate for any diurnal variations in plasma retinoid levels. The authors report that neither the topical treatment with the cream containing retinol nor with the cream containing retinyl palmitate caused significant increases in plasma levels of retinol, retinyl esters, or acids.

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