title: Skin permeation and metabolism of a new antipsoriatic vitamin D(3) analogue of structure 16-en-22-oxa-24-carboalkoxide with low calcemic effect.
abstract: A new vitamin D(3) analogue, SMD-429, is an antipsoriatic candidate of structure 16-en-22-oxa-24-carboalkoxide exhibiting fewer side effects than known vitamin D(3) 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 [(3)H]SMD-429 that SMD-429 was permeated through skin mainly in its metabolized form. The skin permeation profiles of vitamin D(3) 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 x 10(-5) cm(2)/h, which was 10-fold lower than that of maxacalcitol. The apparent metabolic rate constant of SMD-429 in skin was 1.01 x 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 D(3) 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.
authors: Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co Ltd, Gotemba, Shizuoka, Japan. yamaguchikuj@chugai-pharm.co.jp
authors: Koji
authors: K
authors: Yamaguchi
authors: Keiichi
authors: K
authors: Morita
authors: Tetsuya
authors: T
authors: Mitsui
authors: Yoshinori
authors: Y
authors: Aso
authors: Kenji
authors: K
authors: Sugibayashi
mesh_terms: D000818:Animals; D002118:Calcium / Q000097:blood*; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000378:metabolism; D004058:Diffusion; D008297:Male; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption
chemical_list: C529633:SMD-429; D002762:Cholecalciferol; D002118:Calcium