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Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (microD) is the only tool available that explicitly provides data on the extracellular space. Although microD as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of microD in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of microD in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on microD as a tool in drug research and development.

Tissue-targeted metabonomics, or the use of microdialysis sampling with NMR detection, can be used to monitor the metabolic profiles of specific tissues without the need to take tissue biopsies. This allows for sampling from the same animal over the time course of the experiment, reducing animal-to-animal variability and decreasing the number of animals required, however, this approach to metabonomics studies has not been fully characterized. In this work liver microdialysis sampling was performed on male Sprague-Dawley rats and the effects of diurnal rhythms, animal activity and anesthesia on the liver extracellular fluid composition examined. Diurnal rhythms and animal activity caused little change in liver metabolism, but anesthesia caused dramatic effects attributed to the hyperglycemia induced by xylazine and isoflurane. This approach was then applied to the characterization of the hepatotoxicity of doxorubicin, an anticancer agent known to induce oxidative stress. In these studies, two probes were implanted in the liver and doxorubicin was dosed through one of the probes. Comparisons were made between the metabolic profiles from the two probes to distinguish basal metabolic effects from those induced by doxorubicin. Doxorubicin altered hepatic metabolism by different mechanisms in anesthetized and awake rats. These studies also provided important implications for the design of future tissue-targeted metabonomics experiments.

Purpose This study investigated the penetration of lidocaine around and through a sutured incision following the application of iontophoretic and passive patches in the CD Hairless rat. Materials and Methods Concentrations in localized areas (suture, dermis, subcutaneous, and vascular) were determined using microdialysis sampling followed by analysis using liquid chromatography with UV detection. Results Iontophoresis significantly enhanced the dermal penetration of lidocaine. In an intact skin model, dermal concentrations were 40 times greater following iontophoretic delivery compared to passive delivery. In a sutured incision model, iontophoresis enhanced localized concentrations in the dermis, suture, and subcutaneous regions by 6-, 15-, and 20-fold, respectively. Iontophoretic delivery to a region containing a sutured incision was focused to the incision resulting in a greater increase in the suture concentration and in the subcutaneous region directly below the incision. Conclusions The four microdialysis probe design was successful in the determination of localized drug penetration in a sutured incision model. Iontophoresis enhanced skin penetration and allowed for site specific delivery when applied to a sutured incision.