Electroporation and transcutaneous extraction of drugs

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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.