Purpose. The objectives of this work were (a) to explore the potential of transdermal reverse iontophoresis for therapeutic drug monitoring and (b) to develop an "internal standard” calibration procedure so as to render the technique completely noninvasive. Methods. A series of in vitro iontophoresis experiments was performed in which the subdermal concentration of sodium valproate was varied from 21 μM to 1 mM. Glutamic acid was also introduced into the subdermal donor at a fixed concentration to act as an "internal standard” for the calibration method. Results. Both valproate and glutamate anions were recovered, as expected, at the anodal receptor chamber. The iontophoretic extraction flux of valproate was linearly correlated with the subdermal concentration. Glutamate flux was constant. It follows that the ratio of extracted fluxes (valproate/glutamate) was directly dependent upon (a) the subdermal valproate concentration and (b) the subdermal concentration ratio (valproate/glutamate), offering a means, thereby, to a completely noninvasive methodology. Conclusions. This work demonstrates the potential of reverse iontophoresis for noninvasive therapeutic monitoring. The simultaneous quantification of the analyte of interest and of an "internal standard” renders the withdrawal of a blood sample unnecessar
