Increasing tumoral 5-fluorouracil concentrations during a 5-day continuous infusion: a microdialysis study
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.
|Keywords||5-Fluorouracil, Microdialysis, Pharmacokinetics, Target site|
|Persistent URL||dx.doi.org/10.1007/s00280-010-1400-3, hdl.handle.net/1765/20201|
|Journal||Cancer Chemotherapy and Pharmacology|
Konings, I.R.H.M, Sleijfer, S, Matthijsen, R.H.J, de Bruijn, P, Ghobadi Moghadam-Helmantel, I.M, van Dam, L.M, … Loos, W.J. (2011). Increasing tumoral 5-fluorouracil concentrations during a 5-day continuous infusion: a microdialysis study. Cancer Chemotherapy and Pharmacology, 67(5), 1055–1062. doi:10.1007/s00280-010-1400-3