Electroporation and transcutaneous extraction of drugs

描述（由申请人提供）：细胞外液（ECF）中未结合药物的时间过程对于预测抗生素、抗癌药物、抗病毒药物等药物的疗效和毒性至关重要。不幸的是，目前实践的从间质室取样药物的方法是侵入性的和繁琐的。我们建议开发一种无创、简单、快速的“电穿孔和经皮提取（ETE）”方法从真皮ECF中提取药物。ETE是一种通过应用短电脉冲和从皮肤ECF中取样药物来实现皮肤可逆渗透的方法。本申请中提出的研究源于我们最近成功地利用ETE从皮肤ECF中取样药物，如水杨酸、阿昔洛韦、布洛芬、氟康唑和头孢多肟。我们发现ETE测定的皮肤ECF中未结合药物浓度的时间过程与皮肤微透析测定的结果一致。真皮ECF中的布洛芬水平与滑液中的布洛芬水平具有良好的相关性。同样，真皮ECF中未结合的头孢多肟浓度与其在肺组织中的浓度具有良好的相关性。这些结果证明了该方案的可行性。这也支持了我们的目标，即成功开发ETE不仅从治疗皮肤疾病的角度具有重要意义，而且还可以作为罕见组织中药物水平的替代品。本提议的假设是药物经皮提取通量与真皮ECF中未结合药物的浓度成正比。了解皮肤的渗透系数倒数（体内1/P），就可以确定真皮ECF中未结合的药物浓度。我们提出了三个目标，以成功地发展作为一种非侵入性的药物取样技术。在目的1中，我们将通过电解法研究无毛大鼠模型真皮ECF中头孢氨苄、环丙沙星、8-甲氧基补骨脂素和喷昔洛韦的未结合浓度的时间过程。在Aim 2中，我们将通过比较药物在皮肤ECF中的时间过程来评估ETE技术的有效性，该时间过程由ETE测定与皮肤微透析测定。在Aim 3中，我们计划将未结合的头孢氨苄和环丙沙星的时间过程与它们在肺组织中的动力学（通过微透析测定）联系起来。此外，我们还计划将非结合环丙沙星在大鼠真皮ECF中的时间过程与微透析测定的滑液中的时间过程联系起来。

DESCRIPTION (provided by applicant): The time course of unbound drug in the the extracellular fluid (ECF) is critical in predicting the efficacy and toxicity of drugs such as antibiotics, anticancerous, antivirals etc. Unfortunately, the currently practiced methods of sampling drugs from the interstitial compartment are invasive and tedious. We propose to develop a noninvasive, simple and rapid "Electroporation and Transcutaneous extraction (ETE)" to sample the drugs from the dermal ECF. ETE is a method of reversibe permeabilization of skin by the application of short electrical pulses and sampling of drugs from dermal ECF. The research proposed in this application emanates from our recent success in utilizing ETE for sampling of drugs such as salicylic acid, acyclovir, ibuprofen, fluconazole and cefpodoxime from the dermal ECF. We found that the time course of unbound drug concentration in the dermal ECF determined by ETE is in agreement with that determined by dermal microdialysis. The ibuprofen levels in the dermal ECF correlated well with that in the synovial fluid. Similarly the concentration of unbound cefpodoxime in the dermal ECF correlated well with its concentration in the lung tissue. These results demonstrate the feasibility of this project. It also supports our objective that successful development of ETE will not only be signficant from the perspective of treating skin disorders, but also could serve as a surrogate for the drug levels in the rarely accessible tissues. The hypothesis of this proposal is that the transcutaneous extraction flux of drugs is proportional to the concentration of unbound drug in the dermal ECF. Knowing the reciprocal of permeability coefficient (1/P in vivo) of the skin, the unbound drug concentration in the dermal ECF could be determined. We propose three aims for the successful development of ETE as a noninvasive drug sampling technique. In Aim1, we will study the time course of unbound concentration of cephalexin, ciprofloxacin, 8-methoxypsoralen and penciclovir in the dermal ECF by ETE in hairless rat model. In Aim 2, we will assess the validity of ETE technique by comparing the time course of drugs in dermal ECF, determined by ETE with that determined by dermal microdialysis. In Aim 3, we plan to correlate the time course of unbound cephalexin and ciprofloxacin with their kinetics in the lung tissue (determined by microdialysis). Further we also plan to correlate the time course of unbound ciprofloxacin in dermal ECF with that in synovial fluid determined by microdialysis in rat.