LEO Pharma A/S, 2750 Ballerup, Denmark.
Department of Pharmacy, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Mol Pharm. 2021 Aug 2;18(8):3063-3072. doi: 10.1021/acs.molpharmaceut.1c00285. Epub 2021 Jul 11.
Traditionally, cutaneous drug delivery is studied by skin accumulation or skin permeation, while alternative techniques may enable the interactions between the drug and the skin to be studied in more detail. Time-resolved skin profiling for pharmacokinetic monitoring of two Janus Kinase (JAK) inhibitors, tofacitinib and LEO 37319A, was performed using dermal open-flow microperfusion (dOFM) for sampling of perfusate in an and setup in pig skin. Additionally, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) was performed to investigate depth-resolved skin distributions at defined time points in human skin. By dOFM, higher skin concentrations were observed for tofacitinib compared to LEO 37319A, which was supported by the lower molecular weight, higher solubility, lipophilicity, and degree of protein binding. Using MALDI-MSI, the two compounds were observed to show different skin distributions, which was interpreted to be caused by the difference in the ability of the two molecules to interact with the skin compartments. In conclusion, the techniques assessed time- and depth-resolved skin concentrations and were able to show differences in the pharmacokinetic profiles of two JAK inhibitors. Thus, evidence shows that the two techniques can be used as complementary methods to support decision making in drug development.
传统上，皮肤药物传递是通过皮肤积累或皮肤渗透来研究的，而替代技术可能使药物与皮肤之间的相互作用能够更详细地研究。使用真皮开放式微灌注（dOFM）进行采样，在猪皮上进行 和 装置中，对两种 Janus 激酶（JAK）抑制剂托法替尼和 LEO 37319A 进行了时间分辨皮肤分析，以进行药代动力学监测。此外，还进行了基质辅助激光解吸电离质谱成像（MALDI-MSI），以在 时间点研究人体皮肤的深度分辨皮肤分布。通过 dOFM，与 LEO 37319A 相比，观察到托法替尼在皮肤中的浓度更高，这得到了较低分子量、较高溶解度、亲脂性和蛋白质结合程度的支持。使用 MALDI-MSI，观察到两种化合物显示出不同的皮肤分布，这被解释为两种分子与皮肤隔室相互作用的能力差异所致。总之，评估的技术可以实时和深度分辨皮肤浓度，并能够显示两种 JAK 抑制剂的药代动力学特征差异。因此，有证据表明，这两种技术可以作为互补方法，支持药物开发中的决策制定。
