Skin permeation and metabolism of a new antipsoriatic vitamin D3 analogue of structure 16-en-22-oxa-24-carboalkoxide with low calcemic effect

A new vitamin D3 analogue, SMD-429, is an antipsoriatic candidate of structure 16-en-22-oxa-24-carboalkoxide exhibiting fewer side effects than known vitamin D3 analogues. In this study, the permeation of SMD-429 through excised rat skin and three-dimensional cultured human skin model (LSE-high) was evaluated. The cumulative amount of SMD-429 permeated through the skin membranes was lower than that of either maxacalcitol or calcipotriol, whereas the amount of SMD-429 in the skin was the same. It was found from in vitro rat skin permeation experiment using [3H]SMD-429 that SMD-429 was permeated through skin mainly in its metabolized form. The skin permeation profiles of vitamin D3 analogues obtained were analyzed based on a one-layer diffusion model to estimate permeation parameters. The apparent diffusion coefficient of SMD-429 was 1.30 × 10−5 cm2/h, which was 10-fold lower than that of maxacalcitol. The apparent metabolic rate constant of SMD-429 in skin was 1.01 × 10−1 h−1, the same as maxacalcitol. Low apparent diffusivity of SMD-429 in skin might cause an increase in the probability of bioconversion. The same amount of SMD-429 in skin as known vitamin D3 analogues would achieve sufficient therapeutic efficacy in skin. Such low skin permeability and high metabolic conversion in skin of SMD-429 would contribute to a reduction in the systemic side effects.