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Iontophoresis driven concentrations of topically administered diclofenac in skeletal muscle and blood of healthy subjects

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The present open single-centre, descriptive and comparative pharmacokinetic study aimed to investigate the efficacy of iontophoresis to enhance transdermal delivery by measuring concentration vs. time profiles of diclofenac in local tissue and in plasma in two separate study periods.

Methods

Period 1 determined diclofenac concentrations in both calf muscles simultaneously by using microdialysis after applying diclofenac gel topically as a single dose of 5 g with or without iontophoresis in eight healthy volunteers. In period 2, the same dose was applied to another 8 volunteers to determine plasma concentrations of diclofenac either with or without iontophoresis in a cross over design.

Results

In period 1, tissue concentrations were found to be under the limit of detection of 0.5 ng/ml both with and without iontophoresis in all subjects. In period 2, after iontophoresis in 75 % of study participants, plasma concentrations of diclofenac could be determined, but only in 25 % without iontophoresis. Although area under the concentration-time-curve (AUC, 187.97 ± 315.92 vs. 22.92 ± 42.44 ng*min/ml) and maximum concentration (Cmax, 2.06 ± 3.79 vs. 0.22 ± 0.41 ng/ml) values showed a numerically clear trend for higher values with iontophoresis compared to passive diffusion, no significant difference could be found due to high inter-individual variability. In total, 18.75 % of all subjects presented adverse events.

Conclusions

Despite a higher percentage of subjects showed detectable plasma levels of diclofenac after iontophoresis, iontophoresis failed to achieve potentially more effective topical concentrations. The typical mechanism of iontophoresis like electromigration, electroosmosis and increased subcutaneous circulation could be responsible for the results of the present observation. Additional clinical studies are needed to justify the transdermal delivery of diclofenac by using iontophoresis.

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References

  1. Stefanou A, Marshall N, Holdan W, Siddiqui A (2012) A randomized study comparing corticosteroid injection to corticosteroid iontophoresis for lateral epicondylitis. J Hand Surg [Am] 37:104–109

    Article  Google Scholar 

  2. Page MJ, Green S, Kramer S, Johnston RV, McBain B, Buchbinder R (2014 Oct 1) Electrotherapy modalities for adhesive capsulitis (frozen shoulder). Cochrane Database Syst Rev. 10:CD011324. doi: 10.1002/14651858.CD011324. Review

  3. Li GL, Van Steeg TJ, Putter H, Van Der Spek J, Pavel S, Danhof M, Bouwstra JA (2005) Cutaneous side-effects of transdermal iontophoresis with and without surfactant pretreatment: a single-blinded, randomized controlled trial. Br J Dermatol 153:404–412

    Article  CAS  PubMed  Google Scholar 

  4. Barbier P, Mohr P, Muller M, Masciadri R (1998) Efficient fluorination with tetrabutylammonium dihydrogen trifluoride in a novel approach toward 1-alpha-Fluoro-25-hydroxy-vitamin D (3) analogues. J Org Chem 63:6984–6989

    Article  CAS  PubMed  Google Scholar 

  5. Hui X, Anigbogu A, Singh P, Xiong G, Poblete N, Liu P, Maibach HI (2001) Pharmacokinetic and local tissue disposition of [14C] sodium diclofenac following iontophoresis and systemic administration in rabbits. J Pharm Sci 90:1269–1276

    Article  CAS  PubMed  Google Scholar 

  6. Davies NM, Anderson KE (1997) Clinical pharmacokinetics of diclofenac. Therapeutic insights and pitfalls. Clin Pharmacokinet 33:184–213

    Article  CAS  PubMed  Google Scholar 

  7. Zacher J, Altman R, Bellamy N, Brühlmann P, Da Silva J, Huskisson E, Taylor RS (2008) Topical diclofenac and its role in pain and inflammation: an evidence-based review. Curr Med Res Opin 24:925–950

    Article  CAS  PubMed  Google Scholar 

  8. Marnett LJ, Rowlinson SW, Goodwin DC, Kalgutkar AS, Lanzo CA (1999) Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition. J Biol Chem 274:22903–22906

    Article  CAS  PubMed  Google Scholar 

  9. Demirtaş RN, Oner C (1998) The treatment of lateral epicondylitis by iontophoresis of sodium salicylate and sodium diclofenac. Clin Rehabil 12:23–29

    Article  PubMed  Google Scholar 

  10. Joukhadar C, Derendorf H, Muller M (2001) Microdialysis. A novel tool for clinical studies of anti-infective agents. Eur J Clin Pharmacol 57:211–219

    Article  CAS  PubMed  Google Scholar 

  11. Stolley PD, Strom BL (1986) Sample size calculations for clinical pharmacology studies. Clin Pharmacol Ther 39:489–490

    Article  CAS  PubMed  Google Scholar 

  12. Lonnroth P, Jansson PA, Smith U (1987) A microdialysis method allowing characterization of intercellular water space in humans. Am J Physiol 253:E228–231

    CAS  PubMed  Google Scholar 

  13. Muller M, Schmid R, Georgopoulos A, Buxbaum A, Wasicek C, Eichler HG (1995) Application of microdialysis to clinical pharmacokinetics in humans. Clin Pharmacol Ther 57:371–380

    Article  CAS  PubMed  Google Scholar 

  14. Roustit M, Blaise S, Cracowski JL (2014) Trials and tribulations of skin iontophoresis in therapeutics. Br J Clin Pharmacol 77:63–71

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Kalia YN, Naik A, Garrison J, Guy RH (2004) Iontophoretic drug delivery. Adv Drug Deliv Rev 56:619–58

    Article  CAS  PubMed  Google Scholar 

  16. Riecke BF, Bartels EM, Torp-Pedersen S, Ribel-Madsen S, Bliddal H, Danneskiold-Samsøe B, Arendt-Nielsen L (2011) A microdialysis study of topically applied diclofenac to healthy humans: passive versus iontophoretic delivery. Results Pharma Sci 1:76–79

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Marsh CC, Schuna AA, Sundstrom WR (1986) A review of selected investigational nonsteroidal antiinflammatory drugs of the 1980s. Pharmacotherapy 6:10–25

    CAS  PubMed  Google Scholar 

  18. Tashiro Y, Sami M, Shichibe S, Kato Y, Hayakawa E, Itoh K (2001) Effect of lipophilicity on in vivo iontophoretic delivery. II. Beta-blockers. Biol Pharm Bull 24:671–677

    Article  CAS  PubMed  Google Scholar 

  19. Maitani Y, Shimada K, Nagai T (1996) l-Menthol, oleic acid and lauricidin in absorption enhancement of free and sodium salt of diclofenac using ethanol treated silicone membrane as model for skin. Chem Pharm Bull (Tokyo) 44:403–408

    Article  CAS  Google Scholar 

  20. Nishihata T, Kotera K, Nakano Y, Yamazaki M (1987) Rat percutaneous transport of diclofenac and influence of hydrogenated soya phospholipids. Chem Pharm Bull (Tokyo) 35:3807–3812

    Article  CAS  Google Scholar 

  21. Clijsen R, Baeyens JP, Barel AO, Clarys P (2015) In vivo determination of the diclofenac skin reservoir: comparison between passive, occlusive, and iontophoretic application. Drug Des Devel Ther 9:835–840

    Article  PubMed Central  PubMed  Google Scholar 

  22. Tegeder I, Lötsch J, Kinzig-Schippers M, Sörgel F, Kelm GR, Meller ST, Geisslinger G (2001) Comparison of tissue concentrations after intramuscular and topical administration of ketoprofen. Pharm Res 18:980–986

    Article  CAS  PubMed  Google Scholar 

  23. Gallagher EJ, Liebman M, Bijur PE (2001) Prospective validation of clinically important changes in pain severity measured on a visual analog scale. Ann Emerg Med 38:633–638

    Article  CAS  PubMed  Google Scholar 

  24. Massey T, Derry S, Moore RA, McQuay HJ (2010) Topical NSAIDs for acute pain in adults. Cochrane Database Syst Rev 6, CD007402

    PubMed  Google Scholar 

  25. Derry S, Moore RA, Rabbie R (2012) Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database Syst Rev 9, CD007400

    PubMed Central  PubMed  Google Scholar 

  26. Van den Bekerom MP, Sjer A, Somford MP, Bulstra GH, Struijs PA, Kerkhoffs GM (2014 Jan 29) Non-steroidal anti-inflammatory drugs (NSAIDs) for treating acute ankle sprains in adults: benefits outweigh adverse events Knee Surg Sports Traumatol Arthrosc. [Epub ahead of print]

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Acknowledgments

No sources of funding were used to assist in the preparation of this manuscript.

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Physical Medicine and Rehabilitation, Medical University Vienna, Vienna, Austria

    Richard Crevenna, Angela Burian & Mohammad Keilani

  2. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

    Angela Burian, Zoe Oesterreicher, Edith Lackner & Markus Zeitlinger

  3. Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria

    Walter Jäger

  4. Department of Pharmacognosy, University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria

    Gottfried Rezcicek

Authors
  1. Richard Crevenna
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  2. Angela Burian
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  3. Zoe Oesterreicher
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  4. Edith Lackner
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  5. Walter Jäger
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  6. Gottfried Rezcicek
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  7. Mohammad Keilani
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  8. Markus Zeitlinger
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Correspondence to Markus Zeitlinger.

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Crevenna, R., Burian, A., Oesterreicher, Z. et al. Iontophoresis driven concentrations of topically administered diclofenac in skeletal muscle and blood of healthy subjects. Eur J Clin Pharmacol 71, 1359–1364 (2015). https://doi.org/10.1007/s00228-015-1909-9

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  • DOI: https://doi.org/10.1007/s00228-015-1909-9

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