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Open Access 01-05-2011 | Original Article

Increasing tumoral 5-fluorouracil concentrations during a 5-day continuous infusion: a microdialysis study

Authors: Inge R. H. M. Konings, Stefan Sleijfer, Ron H. J. Mathijssen, Peter de Bruijn, Inge M. Ghobadi Moghaddam-Helmantel, Linda M. van Dam, Erik A. C. Wiemer, Jaap Verweij, Walter J. Loos

Published in: Cancer Chemotherapy and Pharmacology | Issue 5/2011

Abstract

Purpose

Response to anticancer therapy is believed to be directly related to the concentration of the anticancer drug in the tumor itself. Assessment of intra-tumor drug pharmacokinetics can be helpful to gain more insight into mechanisms involved in the (in)sensitivity of tumors to anticancer therapy. We explored the pharmacokinetics of 5-fluorouracil in both plasma and tumor tissue during a 5-day continuous infusion of 5-fluorouracil in patients with cancer. Sampling for measurement of 5-fluorouracil in tumor tissue was performed using microdialysis.

Experimental design

In seven patients with an accessible (sub)cutaneous tumor treated with a continuous 5-fluorouracil infusion, plasma and microdialysate samples from tumor and normal adipose tissue were collected over a period of 5 days.

Results

For six patients, drug concentrations in both tumor tissue and plasma were available. Concentration–time curves of unbound 5-fluorouracil were lower in tumor tissue compared to the curves in plasma, but exposure ratios of tumor tissue versus plasma increased during the 5-day infusion period. The presence of circadian rhythmicity of 5-fluorouracil pharmacokinetics in the tumor itself was demonstrated as 5-fluorouracil concentrations in tumor extracellular fluid were higher during the night than during daytime.

Conclusion

Microdialysis was successfully employed in patients with cancer during a continuous 5-day 5-fluorouracil infusion. Plasma and tumor pharmacokinetics of 5-fluorouracil differed substantially with increasing 5-fluorouracil concentrations in tumor over time, possibly resulting from a lowered interstitial fluid pressure by 5-fluorouracil itself. This microdialysis 5-fluorouracil model might be useful to monitor the effect of drug delivery modulating strategies in future studies.

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Title: Increasing tumoral 5-fluorouracil concentrations during a 5-day continuous infusion: a microdialysis study
Authors: Inge R. H. M. Konings
Stefan Sleijfer
Ron H. J. Mathijssen
Peter de Bruijn
Inge M. Ghobadi Moghaddam-Helmantel
Linda M. van Dam
Erik A. C. Wiemer
Jaap Verweij
Walter J. Loos
Publication date: 01-05-2011
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 5/2011
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1400-3

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Abstract

Purpose

Experimental design

Results

Conclusion

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