5--deoxy-5-fluorocytidine and Colorectal-Neoplasms

The aging process is accompanied by physiological changes including reduced glomerular filtration and hepatic function, as well as changes in gastric secretions. To investigate what effect would aging have on the disposition of capecitabine and its metabolites, the pharmacokinetics between patients ≥70 years and <60 years were compared in SWOG0030.. Twenty-nine unresectable colorectal cancer patients were stratified to either ≥70 or <60 years of age, where the disposition of capecitabine and its metabolites were compared.. Notable increase in capecitabine area under the curve (AUC) was accompanied by reduction in capecitabine clearance in ≥70 years patients (P<0.05). No difference in 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine (DFUR), and 5-fluorouracil (5FU) AUCs between the two age groups, suggesting that carboxylesterase and cytidine deaminase (CDA) activity was similar between the two age groups. These results suggest that metabolic enzymes involved in converting capecitabine metabolites are not altered by age. An elevation in capecitabine Cmax and reduction in clearance was seen in females, where capecitabine AUC was 40.3% higher in women. Elevation of DFUR Cmax (45%) and AUC (46%) (P<0.05) was also noted, suggesting that CDA activity may be higher in females.. Increases in capecitabine Cmax and AUC was observed in patients ≥70 years when compared with younger patients who were >60 years.

Topics: Age Factors; Aged; Antimetabolites, Antineoplastic; Area Under Curve; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Floxuridine; Fluorouracil; Glomerular Filtration Rate; Humans; Male; Metabolic Clearance Rate; Middle Aged; Sex Factors

In view of a potential gain in anticancer activity in advanced colorectal cancer (ACRC), there has been considerable interest in using a higher than the approved standard dose of capecitabine (CCB) combined with oxaliplatin. This pharmacokinetic study was designed to evaluate whether CCB is metabolized at the same extent when administered as a monotherapy in two different dose regimens, comparing standard dose (CCB 1) and intensified dose (CCB 2).. Seven patients suffering from ACRC received subsequently two CCB schedules: In the standard schedule, 1,250 mg/m² CCB p.o. twice daily for 2 weeks was administered, after a pause of 1 week, a dose-intensified CCB 2 schedule was given: 1,750 mg/m² CCB p.o. twice daily for 1 week to be followed by 1 week rest. Due to this paired cross over design a direct comparison for each single patient was feasible.. In both schedules, mean peak plasma concentrations of CCB occurred at about 50 min, those of metabolites shortly later (range 54-80 min). Peak plasma concentrations were about 10% (CCB, DFCR) and 40% (DFUR) higher in the CCB 2 regimen. According to the higher dose of CCB in the dose-intensified regimen (+40%), the AUC(last) values increased by 34% (CCB), 20% (DFCR) and 58% (DFUR), respectively.. The results indicate that higher doses of CCB are metabolized approximately dose-dependent compared to the standard dose. No indices for a saturation of metabolizing processes or any significant delay of elimination rate was observed. The immediate 5FU precursor DFUR was formed at a 50% higher extent (expressed as AUC(last) values) than in the standard CCB 1 schedule. From the pharmacokinetic point of view, this increased formation rate suggests clinical importance in regard to metabolic activation of CCB.

Topics: Aged; Antimetabolites, Antineoplastic; Area Under Curve; Capecitabine; Colorectal Neoplasms; Cross-Over Studies; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Floxuridine; Fluorouracil; Humans; Male; Middle Aged

Several retrospective studies have shown that the antitumor efficacy of capecitabine-containing chemotherapy decreases when co-administered with a proton pump inhibitor (PPI). Although a reduction in capecitabine absorption by PPIs was proposed as the underlying mechanism, the effects of PPIs on capecitabine pharmacokinetics remain unclear. We prospectively examined the effects of rabeprazole on the pharmacokinetics of capecitabine and its metabolites.. We enrolled patients administered adjuvant capecitabine plus oxaliplatin (CapeOX) for postoperative colorectal cancer (CRC) patients and metastatic CRC patients receiving CapeOX with/without bevacizumab. Patients receiving a PPI before registration were allocated to the rabeprazole group, and the PPI was changed to rabeprazole (20 mg/day) at least 1 week before the initiation of capecitabine treatment. On day 1, oral capecitabine (1000 mg/m. Five and 9 patients enrolled between September 2017 and July 2018 were allocated to rabeprazole and control groups, respectively. No significant effects of rabeprazole on area under the plasma concentration-time curve divided by capecitabine dose for capecitabine and its three metabolites were observed. Rabeprazole did not affect the proliferation inhibition of colon cancer cells by the respective capecitabine metabolites.. Rabeprazole does not affect capecitabine pharmacokinetics.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Capecitabine; Cell Proliferation; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Deoxycytidine; Drug Interactions; Female; Floxuridine; Fluorouracil; Humans; Male; Middle Aged; Prospective Studies; Proton Pump Inhibitors; Rabeprazole

Drug monitoring is a useful tool for obtaining detailed information about the disposition of a drug in an individual patient during chemotherapy. According to the international guidelines, the analytical assay for quantification of a compound in biological samples must be validated. Among a number of parameters, peak purity is an important requirement.. We analyzed pharmacokinetics in patients who received chemotherapy with capecitabine and up to 10 various co-medications.. Out of seven investigated co-administered drugs, we found evidence that the proton pump inhibitor pantoprazole causes peak interferences with capecitabine during high-performance liquid chromatography analysis. Therefore quantification of capecitabine in plasma samples can be inaccurate.. We recommend an altered time schedule for co-administered drugs or changing the mobile phase used in the assay.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Deoxycytidine; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Floxuridine; Fluorouracil; Humans; Pantoprazole; Proton Pump Inhibitors

Capecitabine, designed as a pro-drug to the cytotoxic agent 5-fluorouracil, is widely used in the management of colorectal cancer. This study was designed to investigate whether co-administration of the monoclonal antibody bevacizumab (BVZ) shows potential to modulate the plasma disposition of capecitabine (CCB) and its metabolites.. Nine patients treated with CCB and BVZ for advanced colorectal cancer entered this pharmacokinetic study. In the first cycle CCB was given alone at doses of 1,250 mg/m2 bi-daily for two weeks with one week rest. In the second cycle BVZ co-administration started simultaneously with oral intake of CCB by short infusion of 7.5 mg/kg.. Mean plasma concentration time curves of CCB and its metabolites were insignificantly lower in the BVZ combination regimen compared to CCB monotherapy. After repeated cycles of BVZ no significant pharmacokinetic interaction was observed.. From the pharmacokinetic point of view and in agreement with numerous clinical study data, co-administration of BVZ with CCB appears to be safe and efficient.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Floxuridine; Fluorouracil; Humans; Male; Middle Aged

A reverse-phase high-performance liquid chromatography method with electrospray ionization and detection by mass spectrometry is described for the simultaneous determination of capecitabine, its intermediate metabolites (DFCR, DFUR) and the active metabolite 5-fluorouracil in mouse plasma, liver and human xenograft tumours. The method was also cross-validated in human plasma and human tumour for clinical application. The method has greater sensitivity than previously published methods with an equivalent accuracy and precision. It uses less biological material (plasma, tissue) and should therefore be applicable to biopsies in patients treated with capecitabine.

Topics: Animals; Capecitabine; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Deoxycytidine; Drug Stability; Floxuridine; Fluorouracil; Humans; Liver; Mice; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization

In metastatic colorectal cancer the oral 5-fluorouracil (5FU) prodrug capecitabine is used with increasing frequency as an alternative to i.v. 5FU administration. The rate of conversion of capecitabine into 5'deoxy-5-fluorouridine has been related to tumor response, and 5FU catabolites have been associated with 5FU-related systemic toxicity. Here we demonstrate for the first time that capecitabine, its metabolites 5'deoxy-5-fluorocytidine and 5'deoxy-5-fluorouridine, and its catabolites 5-fluoro-ureido-propionic acid, alpha-fluoro-beta-alanine, and alpha-fluoro-beta-alanine-bile acid conjugate can be monitored in vivo by (19)fluorine magnetic resonance spectroscopy ((19)F MRS) in the liver of patients with metastatic colorectal cancer. Moreover, we demonstrate an improved signal-to-noise ratio and spectral resolution of the (19)F MRS spectra when measurements are performed at 3 T field strength as compared with measurements at the common clinical field strength of 1.5 T. We conclude that assessment of capecitabine metabolism in patients by (19)F MRS is a promising noninvasive tool for the prediction of its efficacy and toxicity, especially at the now currently available clinical field strength of 3 T.

Topics: Aged; Antimetabolites, Antineoplastic; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Floxuridine; Fluorine; Fluorouracil; Humans; Liver; Liver Neoplasms; Magnetic Resonance Spectroscopy; Male; Middle Aged; Prodrugs