Weiss H Markus, Fresneau Marcel, Moenius Thomas, Stuetz Anton, Billich Andreas
Novartis Pharma AG, Basel, Switzerland.
Drug Metab Dispos. 2008 Sep;36(9):1812-8. doi: 10.1124/dmd.108.021915. Epub 2008 Jun 4.
Pimecrolimus and tacrolimus are calcineurin inhibitors used for the topical treatment of atopic dermatitis. Although structurally similar, they display specific differences including higher lipophilicity and lower skin permeation of pimecrolimus. The aim of the present study was to understand the reason for the differences in skin permeation; in addition, plasma protein binding of the two drugs was analyzed side by side as a basis for comparison of systemic exposure to free drug. Permeation of pimecrolimus and tacrolimus through a silicon membrane was found to be similar; therefore, we assumed that differences in skin permeation could be caused by differences in affinity to skin components. To test this hypothesis, we investigated binding of pimecrolimus and tacrolimus to a preparation of soluble human skin proteins. One binding protein of approximately 15 kDa, probably corresponding to macrophilin12, displayed a similar binding capacity for pimecrolimus and tacrolimus. However, less specific, nonsaturating binding to other proteins was approximately 3-fold higher for pimecrolimus. Because of the high local drug concentration after topical administration, the unspecific, high-capacity binding is probably dominating the permeation through skin. In plasma both drugs bound predominantly to lipoproteins, which may affect disposition differently from albumin binding. The unbound fraction of pimecrolimus in human plasma was approximately 9-fold lower compared with that of tacrolimus (0.4 +/- 0.1 versus 3.7 +/- 0.8%). In conclusion, these results provide an explanation for the observed lower systemic exposure to pimecrolimus than to tacrolimus after topical application and suggest that differences in systemic exposure to free drug might be even more pronounced.
吡美莫司和他克莫司是用于特应性皮炎局部治疗的钙调神经磷酸酶抑制剂。尽管它们结构相似，但存在一些特定差异，包括吡美莫司具有更高的亲脂性和更低的皮肤渗透性。本研究的目的是了解皮肤渗透性差异的原因；此外，同时分析了两种药物的血浆蛋白结合情况，作为比较游离药物全身暴露情况的基础。发现吡美莫司和他克莫司通过硅膜的渗透性相似；因此，我们推测皮肤渗透性的差异可能是由于对皮肤成分的亲和力不同所致。为了验证这一假设，我们研究了吡美莫司和他克莫司与可溶性人皮肤蛋白制剂的结合情况。一种约15 kDa的结合蛋白，可能对应亲免蛋白12，对吡美莫司和他克莫司表现出相似的结合能力。然而，吡美莫司与其他蛋白的非特异性、非饱和结合约高3倍。由于局部给药后药物浓度较高，这种非特异性、高容量结合可能在药物经皮肤渗透过程中起主导作用。在血浆中，两种药物主要与脂蛋白结合，这可能与白蛋白结合对药物处置的影响不同。与他克莫司相比，人血浆中吡美莫司的游离分数约低9倍（0.4±0.1%对3.7±0.8%）。总之，这些结果解释了局部应用后观察到的吡美莫司全身暴露低于他克莫司的现象，并表明游离药物全身暴露的差异可能更为明显。
