The in vivo assessment of drug distribution has long been treated as a “forgotten relative” of pharmacokinetics, mainly due to a lack of appropriate methodology. Research was long restricted to the measurement of drug concentrations from biological specimens that are relatively easy to obtain, or to indirect modelling. However, data obtained by these approaches have resulted in considerable confusion about drug distribution and target site delivery, as their interpretation was flawed by several misconceptions, such as the lack of physiological input to pharmacokinetic models, the erroneous view that a tissue is a uniform matrix, and the notion that the entire drug fraction present in various tissue spaces exerts pharmacological activity. Today, drug distribution to the well defined tissue compartment — “interstitial space fluid”, the biophase for many drugs — can be measured relatively cheaply, minimally invasively, and reproducibly, via microdialysis.
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4.
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MüllerM., SchmidR., GeorgopoulosA., BuxbaumA., WasicekC. & EichlerH.G. (1995). Application of microdialysis to clinical pharmacokinetics in humans. Clinical Pharmacology & Therapeutics57, 371–380.
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BrunnerM., DerendorfH. & MüllerM. (2005). Microdialysis for in vivo pharmacokinetic/pharmacodynamic characterization of anti-infective drugs. Current Opinion in Pharmacology5, 495–499.
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MüllerM., HaagO., BurgdorffT., GeorgopoulosA., WeningerW., JansenB., StanekG., PehambergerH., AgneterE. & EichlerH.G. (1996). Characterization of peripheral-compartment kinetics of antibiotics by in vivo microdialysis in humans. Antimicrobial Agents & Chemotherapy40, 2703–2709.
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LiuP., GrantM., MüllerM. & DerendorfH. (2005). Tissue penetration of cefpodoxime and cefixime in healthy subjects. Journal of Clinical Pharmacology45, 564–569.
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BrunnerM., PernersdorferT., MayerB., EichlerH.G. & MüllerM. (2000). Surgery and intensive care procedures affect the target site distribution of piperacillin. Critical Care Medicine28, 1754–1759.
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DelacherS., DerendorfH., HollensteinU., BrunnerM., JoukhadarC., HofmannS., GeorgopoulosA., EichlerH.G. & MüllerM. (2000). An in vivo pharmacokinetic–in vitro pharmacodynamic approach to simulate target site pharmacodynamics of antibiotics in humans. Journal of Antimicrobial Chemotherapy46, 733–739.
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MüllerM., MaderR.M., SteinerB., StegerG.G., JansenB., GnantM., HelbichT., JakeszR., EichlerH.G. & Blöchl-DaumB. (1997). 5-Fluorouracil kinetics in the interstitial tumor space: clinical response in breast cancer patients. Cancer Research57, 2598–2601.
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MüllerM., BrunnerM., SchmidR., MaderR.M., BockenheimerJ., StegerG.G., SteinerB., EichlerH.G. & Blöchl-DaumB. (1998). Interstitial methotrexate kinetics in primary breast cancer lesions. Cancer Research58, 2982–2985.
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BrunnerM. & MüllerM. (2002). Microdialysis: an in vivo approach for measuring drug delivery in oncology. European Journal of Clinical Pharmacology58, 227–234.
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MüllerM., SchmidR., WagnerO., von OstenB., ShayganfarH. & EichlerH.G. (1995). In vivo characterization of transdermal drug transport by microdialysis. Journal of Controlled Release37, 49–57.
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BenfeldtE., SerupJ. & MennéT. (1999). Effect of barrier perturbation on cutaneous salicylic acid penetration in human skin: in vivo pharmacokinetics using microdialysis and non-invasive quantification of barrier function. British Journal of Dermatology140, 739–748.
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BenfeldtE., HansenS.H., VølundA., MennéT. & ShahV.P. (2007). Bioequivalence of topical formulations in humans: evaluation by dermal microdialysis sampling and the dermatopharmacokinetic method. Journal of Investigative Dermatology127, 170–178.
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LangerO., KarchR., MüllerU., DobrozemskyG., AbrahimA., ZeitlingerM., LacknerE., JoukhadarC., DudczakR., KletterK. & MüllerM. & BrunnerM. (2005). Combined PET and microdialysis for in vivo assessment of intracellular drug pharmacokinetics in humans. Journal of Nuclear Medicine46, 1835–1841.
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LangerO. & MüllerM. (2004). Methods to assess tissue-specific distribution and metabolism of drugs. Current Drug Metabolism5, 463–481.
