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Penetration of capecitabine and its metabolites into malignant and healthy tissues of patients with advanced breast cancer.

Mader RM, Schrolnberger C, Rizovski B, Brunner M, Wenzel C, Locker G, Eichler HG, Mueller M, Steger GG - Br. J. Cancer (2003)

Bottom Line: As intended with the prodrug design of capecitabine, FU was present in low concentrations in tumour interstitium (median c(max): 0.26 microg ml(-1)) when compared with capecitabine, DFCR, and DFUR (median c(max): 2.66, 4.22, and 2.13 microg ml(-1), respectively).Considering tissue exposure at the extracellular level, no significant differences between healthy and malignant tissues were observed.There was no evidence of drug tolerance, which may be attributed to impaired transcapillary transfer into tissue, even after repeated administration as shown for three patients.

View Article: PubMed Central - PubMed

Affiliation: Clinical Division of Oncology, Department of Medicine I, University Hospital, Waehringer Guertel 18-20, Vienna, Austria. robert.mader@akh-wien.ac.at

ABSTRACT
Capecitabine is an oral prodrug of 5-fluorouracil (FU). Since FU concentrations achieved in malignant lesions are an important determinant of efficacy, we investigated the intratumoral transcapillary transfer of capecitabine and its metabolites in vivo. A total of 10 patients with skin metastases from breast cancer received a daily dose of 2500 mg m(-2) capecitabine administered orally in two divided doses for 2 weeks. Microdialysis probes were inserted into a cutaneous metastasis and subcutaneous connective tissue to evaluate the interstitial tissue pharmacokinetics of capecitabine and its metabolites 5'-deoxy-5-fluorocytidine (DFCR), 5'-deoxy-5-fluorouridine (DFUR), and FU by capillary electrophoresis. As intended with the prodrug design of capecitabine, FU was present in low concentrations in tumour interstitium (median c(max): 0.26 microg ml(-1)) when compared with capecitabine, DFCR, and DFUR (median c(max): 2.66, 4.22, and 2.13 microg ml(-1), respectively). Capecitabine and its metabolites easily penetrated malignant and healthy tissue and equilibrated within 45 min between plasma and tissue interstitium. Considering tissue exposure at the extracellular level, no significant differences between healthy and malignant tissues were observed. Our data show that absorption and metabolism determined the tissue pharmacokinetics of capecitabine. There was no evidence of drug tolerance, which may be attributed to impaired transcapillary transfer into tissue, even after repeated administration as shown for three patients.

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Related in: MedlinePlus

Concentration–time profiles of capecitabine and its metabolites in patients with advanced breast cancer. Patients received 1250 mg capecitabine m−2 orally with tap water before collecting plasma samples and interstitial tissue fluid up to 5 h after administration. Concentration–time profile in plasma (A), concentration–time profile in the interstitium of malignant tissue (B), concentration–time profile in the interstitium of subcutaneous connective tissue (C). Concentrations are depicted as means of the single courses ± s.e. (n=10). 5′-DFCR=5′-deoxy-5-fluorocytidine; 5′-DFUR=5′-deoxy-5-fluorouridine; 5-FU=5-fluorouracil.
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fig1: Concentration–time profiles of capecitabine and its metabolites in patients with advanced breast cancer. Patients received 1250 mg capecitabine m−2 orally with tap water before collecting plasma samples and interstitial tissue fluid up to 5 h after administration. Concentration–time profile in plasma (A), concentration–time profile in the interstitium of malignant tissue (B), concentration–time profile in the interstitium of subcutaneous connective tissue (C). Concentrations are depicted as means of the single courses ± s.e. (n=10). 5′-DFCR=5′-deoxy-5-fluorocytidine; 5′-DFUR=5′-deoxy-5-fluorouridine; 5-FU=5-fluorouracil.

Mentions: Values are reported as median and range in parentheses (n=10). DFCR=5′-deoxy-5-fluorocytidine; DFUR=5′-deoxy-5-fluorouridine; FU=5-fluorouracil; cmax=maximum concentration; tmax=time to maximum concentration; t1/2=elimination half-life; AUC0−5 h=area under the concentration-time curve from 0 to 5 h; NA=not applicable.


Penetration of capecitabine and its metabolites into malignant and healthy tissues of patients with advanced breast cancer.

Mader RM, Schrolnberger C, Rizovski B, Brunner M, Wenzel C, Locker G, Eichler HG, Mueller M, Steger GG - Br. J. Cancer (2003)

Concentration–time profiles of capecitabine and its metabolites in patients with advanced breast cancer. Patients received 1250 mg capecitabine m−2 orally with tap water before collecting plasma samples and interstitial tissue fluid up to 5 h after administration. Concentration–time profile in plasma (A), concentration–time profile in the interstitium of malignant tissue (B), concentration–time profile in the interstitium of subcutaneous connective tissue (C). Concentrations are depicted as means of the single courses ± s.e. (n=10). 5′-DFCR=5′-deoxy-5-fluorocytidine; 5′-DFUR=5′-deoxy-5-fluorouridine; 5-FU=5-fluorouracil.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376334&req=5

fig1: Concentration–time profiles of capecitabine and its metabolites in patients with advanced breast cancer. Patients received 1250 mg capecitabine m−2 orally with tap water before collecting plasma samples and interstitial tissue fluid up to 5 h after administration. Concentration–time profile in plasma (A), concentration–time profile in the interstitium of malignant tissue (B), concentration–time profile in the interstitium of subcutaneous connective tissue (C). Concentrations are depicted as means of the single courses ± s.e. (n=10). 5′-DFCR=5′-deoxy-5-fluorocytidine; 5′-DFUR=5′-deoxy-5-fluorouridine; 5-FU=5-fluorouracil.
Mentions: Values are reported as median and range in parentheses (n=10). DFCR=5′-deoxy-5-fluorocytidine; DFUR=5′-deoxy-5-fluorouridine; FU=5-fluorouracil; cmax=maximum concentration; tmax=time to maximum concentration; t1/2=elimination half-life; AUC0−5 h=area under the concentration-time curve from 0 to 5 h; NA=not applicable.

Bottom Line: As intended with the prodrug design of capecitabine, FU was present in low concentrations in tumour interstitium (median c(max): 0.26 microg ml(-1)) when compared with capecitabine, DFCR, and DFUR (median c(max): 2.66, 4.22, and 2.13 microg ml(-1), respectively).Considering tissue exposure at the extracellular level, no significant differences between healthy and malignant tissues were observed.There was no evidence of drug tolerance, which may be attributed to impaired transcapillary transfer into tissue, even after repeated administration as shown for three patients.

View Article: PubMed Central - PubMed

Affiliation: Clinical Division of Oncology, Department of Medicine I, University Hospital, Waehringer Guertel 18-20, Vienna, Austria. robert.mader@akh-wien.ac.at

ABSTRACT
Capecitabine is an oral prodrug of 5-fluorouracil (FU). Since FU concentrations achieved in malignant lesions are an important determinant of efficacy, we investigated the intratumoral transcapillary transfer of capecitabine and its metabolites in vivo. A total of 10 patients with skin metastases from breast cancer received a daily dose of 2500 mg m(-2) capecitabine administered orally in two divided doses for 2 weeks. Microdialysis probes were inserted into a cutaneous metastasis and subcutaneous connective tissue to evaluate the interstitial tissue pharmacokinetics of capecitabine and its metabolites 5'-deoxy-5-fluorocytidine (DFCR), 5'-deoxy-5-fluorouridine (DFUR), and FU by capillary electrophoresis. As intended with the prodrug design of capecitabine, FU was present in low concentrations in tumour interstitium (median c(max): 0.26 microg ml(-1)) when compared with capecitabine, DFCR, and DFUR (median c(max): 2.66, 4.22, and 2.13 microg ml(-1), respectively). Capecitabine and its metabolites easily penetrated malignant and healthy tissue and equilibrated within 45 min between plasma and tissue interstitium. Considering tissue exposure at the extracellular level, no significant differences between healthy and malignant tissues were observed. Our data show that absorption and metabolism determined the tissue pharmacokinetics of capecitabine. There was no evidence of drug tolerance, which may be attributed to impaired transcapillary transfer into tissue, even after repeated administration as shown for three patients.

Show MeSH
Related in: MedlinePlus