Iontophoresis is the application of a small electric current to enhance the transport of both charged and polar, neutral compounds across the skin. Manipulation of either the total charge delivered and/or certain electrode formulation parameters allows control of electromigration and electroosmosis, the two principal mechanisms of transdermal iontophoresis. While the approach has been mainly used for transdermal drug delivery, 'reverse iontophoresis', by which substances are extracted to the skin surface, has recently been the subject of considerable effort. Glucose monitoring has been extensively studied and other applications, including therapeutic drug monitoring, are contributing to the development of the technique. An internal standard calibration procedure may ultimately render this novel monitoring technique completely non-invasive.

Background:We investigated reverse transdermal iontophoresis as an alternative, noninvasive method for lithium monitoring in vivo. The objectives of such an approach would be to facilitate compliance with treatment and to improve the quality of life for bipolar patients. Methods: We studied 23 bipolar or schizo-affective patients. Over a 2-h period, we extracted lithium and other cations across intact skin by application of an electric current (0.8 mA) and quantified the concentrations by ion chromatography. A blood sample provided comparative reference values for the drug and other electrolytes. Results: Lithium, sodium, potassium, and calcium were efficiently extracted by iontophoresis. Lithium extraction fluxes were proportional to the corresponding serum concentrations, whereas sodium, potassium, and calcium extraction fluxes were relatively constant, consistent with their stable concentrations in blood. Normalization of the lithium extraction flux with that of sodium, which acted as an "internal standard", permitted calibration of the monitoring procedure without the need for a blood measurement. This conclusion was tested retrospectively by dividing the patients into two groups. The reverse iontophoretic extraction data from the first subset (a) established the proportionality between lithium iontophoresis (or the relative electrotransport of lithium and sodium) and (b) predicted lithium blood concentrations in the second subset of patients. The predictive ability was very good, with the internal standard concept providing substantial benefit.

Purpose. Transdermal iontophoresis was investigated as a noninvasive tool for drug monitoring and pharmacokinetic profiling. Lithium, a frequently monitored drug, was used as a model. The objectives were a) to demonstrate the linear dependence of the iontophoretic extraction flux of lithium on the subdermal concentration of the drug, b) to evaluate the capacity of iontophoresis to monitor sudden changes in the subdermal level, c) to investigate the utility of reverse iontophoresis as a tool in pharmacokinetic studies, and d) to examine the validity of an internal standard calibration procedure to render the method completely noninvasive. Methods. Transdermal, iontophoretic extraction was performed in vitro using dermatomed pig-ear skin. The subdermal solution consisted of a physiological buffer containing lithium chloride at concentrations in the therapeutic range and two putative internal standards, sodium and potassium, at fixed physiological levels. The subdermal concentration of lithium was changed either in a stepwise fashion or by simulating one of two pharmacokinetic profiles. Results. Lithium was extracted via electromigration to the cathode. A excellent correlation between subdermal lithium concentration and iontophoretic extraction flux was observed. Iontophoresis tracked sudden concentration changes and followed kinetic profiles. In addition, the effective elimination rate constant could be directly, and noninvasively, estimated from the extraction flux data. Conclusions. Reverse iontophoresis is a potentially useful and noninvasive tool for lithium monitoring.

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