Application of Microdialysis in Assessing Cutaneous Bioavailability

  • Eva BenfeldtEmail author


This chapter gives a review of microdialysis sampling in the skin with an emphasis on dermal sampling and use in bioequivalence assessment of topical formulations. Microdialysis as a research technique is suitable for a number of different study designs for sampling in the skin or subcutaneous tissues. This versatility includes the option of conducting preclinical studies in animals as well as ex vivo human skin set-ups. The effect of even small alterations in a topical formulation can be detected by simultaneous sampling in several areas in the same person, enabling studies of bioavailability and bioequivalence in study groups of relatively few volunteers or patients. Whenever the dermis is the target tissue, dermal microdialysis can be considered the method of choice for acquisition of human in vivo data.


Bioequivalence Study Probe Depth Guide Cannula Skin Barrier Function Clobetasol Propionate 
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  1. 1.
    Au WL, Skinner MF, Benfeldt E, Verbeeck RK, Kanfer I. Application of dermal microdialysis for the determination of bioavailability of clobetasol propionate applied to the skin of human subjects. Skin Pharmacol Physiol. 2012;25(1):17–24. doi:10.1159/000330489.CrossRefPubMedGoogle Scholar
  2. 2.
    Ault JM, Riley CM, Meltzer NM, Lunte CE. Dermal microdialysis sampling in vivo. Pharm Res. 1994;11(11):1631–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Benfeldt E. in vivo microdialysis for the investigation of drug levels in the dermis and the effect of barrier perturbation on cutaneous drug penetration. Studies in hairless rats and human subjects. Acta Derm Venereol. 1999;206:1–59. Scholar
  4. 4.
    Benfeldt E, Groth L. Feasibility of measuring lipophilic or protein-bound drugs in the dermis by in vivo microdialysis after topical or systemic drug administration. Acta Derm Venereol. 1998;78(4):274–8. Scholar
  5. 5.
    Benfeldt E, Serup J. Effect of barrier perturbation on cutaneous penetration of salicylic acid in hairless rats: in vivo pharmacokinetics using microdialysis and non-invasive quantification of barrier function. Arch Dermatol Res. 1999;291(9):517–26. Scholar
  6. 6.
    Benfeldt E, Serup J, Menné T. Effect of barrier perturbation on cutaneous salicylic acid penetration in human skin: in vivo pharmacokinetics using microdialysis and non-invasive quantification of barrier function. Br J Dermatol. 1999a;140(4):739–48. Scholar
  7. 7.
    Benfeldt E, Serup J, Menné T. Microdialysis vs. suction blister technique for in vivo sampling of pharmacokinetics in the human dermis. Acta Derm Venereol. 1999b;79(5):338–42. Scholar
  8. 8.
    Benfeldt E, Hansen SH, Vølund A, Menné T, Shah VP. Bioequivalence of topical formulations in humans: evaluation by dermal microdialysis sampling and the dermatopharmacokinetic method. J Invest Dermatol. 2007;127(1):170–8. doi:10.1038/sj.jid.5700495.Google Scholar
  9. 9.
    Borg N, Götharson E, Benfeldt E, Groth L, Ståhle L. Distribution to the skin of penciclovir after oral famciclovir administration in healthy volunteers: comparison of the suction blister technique and cutaneous microdialysis. Acta Derm-Venereol. 1999;79(4):274–7. Scholar
  10. 10.
    Boutsiouki P, Thompson J, Clough G. Effects of local blood flow on the percutaneous absorption of the organophosphorus compound malathion: a microdialysis study in man. Arch Toxicol. 2001;75(6):321–8. doi:10.1007/s002040100245.CrossRefPubMedGoogle Scholar
  11. 11.
    Brunner M, Davies D, Martin W, Leuratti C, Lackner E, Müller M. A new topical formulation enhances relative diclofenac bioavailability in healthy male subjects. Br J Clin Pharmacol. 2011;71(6):852–9. doi:10.1111/j.1365-2125.2011.03914.x.CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Chaturvedula A, Joshi DP, Anderson C, Morris R, Sembrowich WL, Banga AK. Dermal, subdermal, and systemic concentrations of granisetron by iontophoretic delivery. Pharm Res. 2005;22(8):1313–9. doi:10.1007/s11095-005-5335-z.CrossRefPubMedGoogle Scholar
  13. 13.
    Chaurasia CS, Müller M, Bashaw ED, Benfeldt E, Bolinder J, Bullock R, Bungay PM, et al. AAPS-FDA workshop white paper: microdialysis principles, application and regulatory perspectives. Pharm Res. 2007;24(5):1014–25. Scholar
  14. 14.
    Clough GF, Boutsiouki P, Church MK, Michel CC. Effects of blood flow on the in vivo recovery of a small diffusible molecule by microdialysis in human skin. J Pharmacol Exp Ther. 2002;302(2):681–6. doi:10.1124/jpet.102.035634.samplingCrossRefPubMedGoogle Scholar
  15. 15.
    Fulzele SV, Babu RJ, Ahaghotu E, Singh M. Estimation of proinflammatory biomarkers of skin irritation by dermal microdialysis following exposure with irritant chemicals. Toxicol. 2007;237(1–3):77–88. Scholar
  16. 16.
    Garcia Ortiz P, Hansen SH, Shah VP, Menné T, Benfeldt E. Impact of adult atopic dermatitis on topical drug penetration: assessment by cutaneous microdialysis and tape stripping. Acta Derm Venereol. 2009;89(1):33–8. doi:10.2340/00015555-0562.CrossRefPubMedGoogle Scholar
  17. 17.
    García Ortiz P, Hansen SH, Shah VP, Sonne J, Benfeldt E. Are marketed topical metronidazole creams bioequivalent? Evaluation by in vivo microdialysis sampling and tape stripping methodology. Skin Pharmacol Physiol. 2011;24(1):44–53. doi:10.1159/000320151.CrossRefPubMedGoogle Scholar
  18. 18.
    Groth L, Serup J. Cutaneous microdialysis in man: effects of needle insertion trauma and anaesthesia on skin perfusion, erythema and skin thickness. Acta Derm-Venereol. 1998;78(1):5–9. Scholar
  19. 19.
    Hegemann L, Forstinger C, Partsch B. Microdialysis in cutaneous pharmacology: kinetic analysis of transdermally delivered nicotine. J Invest Dermatol. 1995;104(5):838–43. Scholar
  20. 20.
    Holmgaard R, Nielsen JB, Benfeldt E. Microdialysis sampling for investigations of bioavailability and bioequivalence of topically administered drugs: current state and future perspectives. Skin Pharmacol Physiol. 2010;23(5):225–43. doi:10.1159/000314698.CrossRefPubMedGoogle Scholar
  21. 21.
    Holmgaard R, Benfeldt E, Bangsgaard N, Sorensen JA, Brosen K, Nielsen F, Nielsen JB. Probe depth matters in dermal microdialysis sampling of benzoic acid after topical application: an ex vivo study in human skin. Skin Pharmacol Physiol. 2012;25(1):9–16. doi:10.1159/000330491.CrossRefPubMedGoogle Scholar
  22. 22.
    Holmgaard R, Benfeldt E, Nielsen JB, Gatschelhofer C, Sorensen JA, Höfferer C, Bodenlenz M, et al. Comparison of open-flow microperfusion and microdialysis methodologies when sampling topically applied fentanyl and benzoic acid in human dermis ex vivo. Pharm Res. 2012;29(7):1808–20. doi:10.1007/s11095-012-0705-9.CrossRefPubMedGoogle Scholar
  23. 23.
    Incecayir T, Agabeyoglu I, Derici U, Sindel S. Assessment of topical bioequivalence using dermal microdialysis and tape stripping methods. Pharm Res. 2011;28(9):2165–75. doi:10.1007/s11095-011-0444-3.CrossRefPubMedGoogle Scholar
  24. 24.
    Kellogg DL, Zhao JL, Wu Y. Neuronal nitric oxide synthase control mechanisms in the cutaneous vasculature of humans in vivo. J Physiol. 2008;586(3):847–57. doi:10.1113/jphysiol.2007.144642.CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Klimowicz A, Farfal S, Bielecka-Grzela S. Evaluation of skin penetration of topically applied drugs in humans by cutaneous microdialysis: acyclovir vs. salicylic acid. J Clin Pharm Ther. 2007;32(2):143–8. doi:10.1111/j.1365-2710.2007.00803.x.CrossRefPubMedGoogle Scholar
  26. 26.
    Kreilgaard M. Dermal pharmacokinetics of microemulsion formulations determined by in vivo microdialysis. Pharm Res. 2001;18(3):367–73. Scholar
  27. 27.
    Kreilgaard M, Kemme MJ, Burggraaf J, Schoemaker RC, Cohen AF. Influence of a microemulsion vehicle on cutaneous bioequivalence of a lipophilic model drug assessed by microdialysis and pharmacodynamics. Pharm Res. 2001;18(5):593–9. Scholar
  28. 28.
    Krogstad A, Lonnroth P, Larson G, Wallin BG. Increased interstitial histamine concentration in the psoriatic plaque. J Invest Dermatol. 1997;109:632–5. Scholar
  29. 29.
    Lionberger RA. FDA critical path initiatives: opportunities for generic drug development. AAPS J. 2008;10(1):103–9. doi:10.1208/s12248-008-9010-2.CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    McCleverty D, Lyons R, Henry B. Microdialysis sampling and the clinical determination of topical dermal bioequivalence. Int J Pharm. 2006;308(1–2):1–7. doi:10.1016/j.ijpharm.2005.09.020.CrossRefPubMedGoogle Scholar
  31. 31.
    Morgan CJ, Renwick AG, Friedmann PS. The role of stratum corneum and dermal microvascular perfusion in penetration and tissue levels of water-soluble drugs investigated by microdialysis. Br J Dermatol. 2001;148(3):434–43.CrossRefGoogle Scholar
  32. 32.
    Mugglestone CJ, Mariz S, Lane ME. The development and registration of topical pharmaceuticals. Int J Pharm. 2012;435(1):22–6. doi:10.1016/j.ijpharm.2012.03.052.CrossRefPubMedGoogle Scholar
  33. 33.
    Müller M, Schmid R, Wagner O, Osten v. B., Shayganfar H, Eichler GH. In vivo characterization of transdermal drug transport by microdialysis. J Control Release. 1995;37:49–57Google Scholar
  34. 34.
    Müller M, Mascher H, Kikuta C, Schäfer S, Brunner M, Dorner G, Eichler HG. Diclofenac concentrations in defined tissue layers after topical administration. Clin Pharmacol Ther. 1997;62(3):293–9. doi:10.1016/S0009-9236(97)90032-1.CrossRefPubMedGoogle Scholar
  35. 35.
    Ortiz PG, Hansen SH, Shah VP, Menné T, Benfeldt E. The effect of irritant dermatitis on cutaneous bioavailability of a metronidazole formulation, investigated by microdialysis and dermatopharmacokinetic method. Contact Dermat. 2008;59(1):23–30. doi:10.1111/j.1600-0536.2008.01348.x.CrossRefGoogle Scholar
  36. 36.
    Sandberg C, Halldin CB, Ericson MB, Larkö O, Krogstad AL, Wennberg AM. Bioavailability of aminolaevulinic acid and methylaminolaevulinate in basal cell carcinomas: a perfusion study using microdialysis in vivo. Br J Dermatol. 2008;159(5):1170–6. doi:10.1111/j.1365-2133.2008.08795.x.PubMedGoogle Scholar
  37. 37.
    Seki T, Wang A, Yuan D, Saso Y, Hosoya O, Chono S, Morimoto K. Excised porcine skin experimental systems to validate quantitative microdialysis methods for determination of drugs in skin after topical application. J Control Release. 2004;100(2):181–9. doi:10.1016/j.jconrel.2004.08.016.CrossRefPubMedGoogle Scholar
  38. 38.
    Shah V, Flynn G, Yacobi A. Bioequivalence of topical dermatological dosage forms-methods of evaluation of bioequivalence. Skin Pharmacol Appl Skin Physiol. 1998;11(2):117–24. Scholar
  39. 39.
    Shinkai N, Korenaga K, Okumura Y, Mizu H, Yamauchi H. Microdialysis assessment of percutaneous penetration of ketoprofen after transdermal administration to hairless rats and domestic pigs. Eur J Pharm Biopharm. 2011;78(3):415–21. doi:10.1016/j.ejpb.2011.03.005CrossRefPubMedGoogle Scholar
  40. 40.
    Simonsen L, Jørgensen A, Benfeldt E, Groth L. Differentiated in vivo skin penetration of salicylic compounds in hairless rats measured by cutaneous microdialysis. Eur J Pharm Sci. 2004;21(2–3):379–88. doi:10.1016/j.ejps.2003.11.004.CrossRefPubMedGoogle Scholar
  41. 41.
    Stenken JA, Church, MK, Gill CA, Clough GF. How minimally invasive is microdialysis sampling? A cautionary note for cytokine collection in human skin and other clinical studies. AAPS J. 2010;12(1):73–8. doi:10.1208/s12248-009-9163-7.CrossRefPubMedCentralPubMedGoogle Scholar
  42. 42.
    Sun L, Stenken JA. Improving microdialysis extraction efficiency of lipophilic eicosanoids. J Pharm Biomed Anal. 2003;33(5):1059–71. doi:10.1016/S0731-7085(03)00363-7.CrossRefPubMedGoogle Scholar
  43. 43.
    Tegeder I, Muth-Selbach U, Lötsch J, Rüsing G, Oelkers R, Brune K, Meller S, Kelm GR, Sörgel F, Geisslinger G. Application of microdialysis for the determination of muscle and subcutaneous tissue concentrations after oral and topical ibuprofen. Clin Pharmacol Therapeut. 1999;(65):357–68. doi:10.1016/S0009-9236(99)70128-1.CrossRefGoogle Scholar
  44. 44.
    Tegeder I, Lötsch J, Kinzig-Schippers M, Sörgel F, Kelm GR, Meller ST, Geisslinger G. Comparison of tissue concentrations after intramuscular and topical administration of ketoprofen. Pharm Res. 2001;18(7):980–6. Scholar
  45. 45.
    Tettey-Amlalo RNO, Kanfer I, Skinner MF, Benfeldt E, Verbeeck RK. Application of dermal microdialysis for the evaluation of bioequivalence of a ketoprofen topical gel. Eur J Pharma Sci. 2009;36(2–3):219–25. doi:10.1016/j.ejps.2008.09.002.CrossRefGoogle Scholar
  46. 46.
    Ward KW, Medina SJ, Portelli ST, Mahar Doan KM, Spengler MD, Ben MM, Lundberg D, et al. Enhancement of in vitro and in vivo microdialysis recovery of SB-265123 using Intralipid and Encapsin as perfusates. Biopharm Drug Dispos. 2003;24(1):17–25. doi:10.1002/bdd.332.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Dermatology, Faculty of Health SciencesUniversity of Copenhagen, Roskilde HospitalRoskildeDenmark

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