Is It Important to Model the Impact of Blood Flow on the Dose of Drugs Delivered Transcutaneously

law, the dose of drug delivered to the skin is controlled. Iontophoresis uses a small electric current to drive charged substances into the skin. Electromigration of ions during iontophoresis has also been shown to induce osmotic water flow and the convective movement of neutral or even charged molecules – a process termed electro-osmosis. It is generally held that the quantity of drug delivered depends on the magnitude and duration of the current applied, the driving force (voltage) required to achieve this dose depending on the nature of the structure of the skin and its compartments. Human skin consists of three main layers – the epidermis, dermis and hypodermis. While the stratum corneum of the epidermis, with its structured lipophilic and hydrophilic domains, constitutes the major rate-limiting layer for transdermal delivery of drugs, the dermis and its vasculature, which act as the systemic absorption site for iontophoresed drugs, present the greatest challenge when modelling transdermal iontophoretic transport. The movement of agents into and within the dermis is subject to many variables, including diffusive and electrorepulsive forces at the epidermal barrier, protein/receptor binding and drug metabolism which together modulate the presence of ‘ambient’ ions in the skin that contribute to the current flow which defines drug dose. The assessment of endothelial responsiveness to vasodilator stimuli has long been considered a surrogate by which to evaluate cardiovascular risk. Our understanding of the endothelial phenotype in health and disease and the impact or therapeutic intervention on endothelial function are largely based on the measurement of changes in vessel diameter and/or perfusion in the peripheral vasculature following perturbation using physiological and pharmacological stimuli. These tests need to be non-invasive, reproducible, repeatable and standardized between laboratories if they are to be of clinical value [1] . They also should not modulate endothelial vascular function by themselves. At the level of the microvasculature, these tests generally involve perturbation of the vasculature using reactive hyperaemia, local warming, or introduction of pharmacological agents and the subsequent monitoring of the vasoresponse [2] . Iontophoretic delivery of vaso-active substances to the skin combined with laser Doppler flowmetry or perfusion imaging has been widely used for the assessment of vascular endothelial function in both research and clinical settings. The recognized advantages of the technique are that drug delivery is non-invasive and local, thus avoiding tissue perturbation and/or systemic drug effects, and that, by controlling the duration and magnitude of the iontophoretic current based on Coulomb’s Published online: November 25, 2008