The objectives of this project are (1) to mechanistically quantify the causes of flux variability during conventional constant current DC transdermal iontophoresis and (2) to overcome this problem so constant and precise iontophoretic transport can be achieved and maintained for the treatment of different diseases. Inter-subject and intra-subject variability during conventional constant current direct current (DC) transdermal iontophoresis has been noted in the literature but has not been addressed. The importance of controlling and maintaining a constant transdermal iontophoretic flux (i.e., a constant drug administration rate or constant extraction rate) has also been demonstrated in recent iontophoresis advances. An example is the new non-invasive "reverse" iontophoresis blood glucose monitoring system for the management of diabetes. This new technology can improve the quality of life of diabetics but suffers from flux variability that results in long equilibration time and frequent finger-stick calibrations. For iontophoretic extraction of compounds from the body in therapeutic monitoring and systemic delivery of drugs having narrow therapeutic windows, flux variability has posed major challenges to pharmaceutical scientists and limited the potential benefit of what transdermal iontophoresis can bring to the health of the public. In the present project, we propose to test the hypothesis that flux variability is a result of the changes in skin electrical resistance accompanying pore size, pore charge, and/or pore pathway alterations during iontophoresis. We will also test a new constant skin electrical resistance approach to overcome this flux variability problem. The information obtained in this project will help pharmaceutical scientists better predict and control transdermal iontophoretic flux in systemic drug delivery and extraction of compounds from the body for the treatment, diagnosis, and monitoring of different diseases. Our results will also advance the knowledge of the transport mechanisms and the barrier properties of the skin pathways during iontophoresis for future strategy development to enhance iontophoretic transport.