Evaluation of plasma 5-fluorouracil nucleoside levels in patients with metastatic breast cancer: relationships with toxicities

Abstract

This paper describes the relationship between 5-fluorouracil (FUra)-derived toxicities and plasma levels of the FUra anabolites 5-fluorouridine (FUrd) and 5-fluoro-2'-deoxyuridine (FdUrd) monitored in patients receiving continuous infusions of FUra (1000 mg/m2 per 24 h) over 5 days preceded by the administration of cisplatin (100 mg/m2). A total of 63 courses of this treatment were given as second-line chemotherapy to 17 patients with metastatic breast cancer. The active FUra anabolites FUrd and FdUrd were monitored twice daily in the plasma by high-performance liquid chromatography. Data were analyzed using multiple analysis of variance (ANOVA). Only a low proportion of patients exhibited measurable plasmatic levels of FUrd (43%) and FdUrd (70%). The areas under the plasma concentration-time curves (AUC) determined over 120 h for FUrd (AUCFUrd) and for FdUrd (AUCFdUrd) were found to be statistically significantly different for chemotherapy cycles with and those without myelosuppression. Chemotherapy cycles without neutropenia were associated with low AUCFUrd values (mean +/- SEM, 2.9 +/- 0.7 micrograms ml-1 h) and high AUCFdUrd values (14.1 +/- 2.7 micrograms ml-1 h), respectively, whereas courses with myelosuppression (WHO grades 2-4) showed inverse profiles with high AUCFUrd values (16.3 +/- 2.3 micrograms ml-1 h) and low AUCFdUrd values (3.1 +/- 1.0 micrograms ml-1 h), respectively. A statistically significant difference in AUCFdUrd values was also observed between cycles with and those without mucositis (P = 0.0027), with AUCFdUrd values being 22.6 +/- 5.6 and 7.8 +/- 1.9 micrograms ml-1 h, respectively. Whereas hematotoxicity could be correlated with both AUCFUrd and AUCFdUrd values, mucositis was associated with high AUCFdUrd levels. Moreover, a negative correlation was found between the AUCs determined for FUrd and FdUrd (P = 0.002), indicating that activation of FUra via FUrd or via FdUrd may involve competitive processes. Therefore, to follow the development of the major FUra-derived toxicities, measurement of FUrd and FdUrd plasma levels appeared very attractive.

A simultaneous determination method for 5‐fluorouracil and its metabolites in human plasma with linear range adjusted by in‐source collision‐induced dissociation using hydrophilic interaction liquid chromatography–electrospray ionization–tandem mass spectrometry

“…S1 in the Supporting Information) simultaneously in human plasma. Although pharmacokinetic parameters of 5‐FU and its metabolites have correlated anticancer effect and/or adverse effects (Barberi‐Heyob et al ., ; Bocci et al ., ; Gamelin et al ., ; Yamada et al ., ), no simultaneous determination method has yet been reported since differences in physicochemical properties force us to use multiple assay methods suitable for each metabolite (Deenen et al ., ). Therefore, it is very important to obtain a simultaneous quantitative determination method for analysis of 5‐FU and its metabolites in human plasma.…”

“…S1 in the Supporting Information) simultaneously in human plasma. Although pharmacokinetic parameters of 5-FU and its metabolites have correlated anticancer effect and/or adverse effects (Barberi-Heyob et al, 1995;Bocci et al, 2006;Gamelin et al, 2008;Yamada et al, 2003), no simultaneous determination method has yet been reported since differences in physicochemical properties force us to use multiple assay methods suitable for * Correspondence to: Mano, Nariyasu, Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. Email: mano@hosp.tohoku.ac.jp each metabolite (Deenen et al, 2013).…”