Mortensen J T, Lichtenberg J, Binderup L
Biological Research and Development, Leo Pharmaceutical Products, Ballerup, Denmark.
J Investig Dermatol Symp Proc. 1996 Apr;1(1):60-3.
To investigate and compare the effects on calcium metabolism of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and the synthetic vitamin D analogs tacalcitol and calcipotriol after topical treatment, we treated groups of rats topically once daily with three dose levels of each test compound in a vehicle of propylene glycol plus ethanol for 28 d. The urinary calcium excretion was measured after 14 d, and serum calcium and parathyroid hormone were measured at termination. The rats were autopsied, and the kidneys were examined microscopically for mineralizations. Based on the urinary calcium excretion and the serum calcium level, calcipotriol was found to be 60 times less calcemic, and tacalcitol was slightly less calcemic, than 1,25(OH)2D3 after repeated topical application to rats. Serum parathyroid hormone was suppressed to a lower degree by calcipotriol and tacalcitol than by 1,25(OH)2D3, and the incidence and severity of renal corticomedullary mineralization were higher in rats treated with 1,25(OH)2D3 and tacalcitol than with calcipotriol. We conclude that calcipotriol is much less calcemic than 1,25(OH)2D3 or tacalcitol when applied topically to rats in a vehicle that enhances penetration into the skin. We attribute the lower calcemic effect of calcipotriol to the pharmacokinetic profile of the compound, particularly its rapid metabolization into inactive compounds.
为了研究和比较局部治疗后1,25 - 二羟基维生素D3（1,25(OH)2D3）以及合成维生素D类似物他卡西醇和卡泊三醇对钙代谢的影响，我们将大鼠分组，每天一次用三种剂量水平的每种受试化合物在丙二醇加乙醇的赋形剂中进行局部治疗，持续28天。在14天后测量尿钙排泄量，并在实验结束时测量血清钙和甲状旁腺激素。对大鼠进行尸检，并对肾脏进行显微镜检查以观察矿化情况。基于尿钙排泄量和血清钙水平，发现对大鼠反复局部应用后，卡泊三醇的致血钙升高作用比1,25(OH)2D3低60倍，他卡西醇的致血钙升高作用略低于1,25(OH)2D3。与1,25(OH)2D3相比卡泊三醇和他卡西醇对血清甲状旁腺激素的抑制程度较低，并且用1,25(OH)2D3和他卡西醇治疗的大鼠肾皮质髓质矿化的发生率和严重程度高于用卡泊三醇治疗的大鼠。我们得出结论，当在增强皮肤渗透的赋形剂中对大鼠进行局部应用时，卡泊三醇的致血钙升高作用比1,25(OH)2D3或他卡西醇低得多。我们将卡泊三醇较低的致血钙升高作用归因于该化合物的药代动力学特征，特别是其快速代谢为无活性化合物。
