2--2--difluoro-2--deoxyuridine and Adenocarcinoma

Gemcitabine (2,2-difluorodeoxycytidine [dFdC]) can be administered in a standard 30-minute infusion or in a fixed-dose-rate (FDR) infusion to maximize the rate of accumulation of triphosphate, its major intracellular metabolite. The standard 30-minute infusion requires dose adjustment in patients with organ dysfunction, especially in patients with elevated baseline serum bilirubin levels. On the other hand, the FDR infusion is burdened by increased haematological toxicity. The primary aim of this study was to evaluate the pharmacokinetics of dFdC and its metabolite difluorodeoxyuridine (dFdU) in patients with normal and impaired hepatic function.. In this prospective study, patients with pancreatic or biliary tract carcinoma and normal or impaired hepatic function tests were considered eligible for recruitment. Patients were recruited according to the following criteria: (i) serum bilirubin <1.6 mg/dL and AST and ALT <2 times the upper the limit of normal (ULN) [cohort I]; and (ii) serum bilirubin >1.6 mg/dL and/or AST/ALT >2 times the ULN (cohort II). An FDR infusion of gemcitabine 1000 mg/m2 was administered on days 1, 8 and 15 every 4 weeks. The pharmacokinetic analysis of gemcitabine and dFdU was performed with high-performance liquid chromatography-tandem mass spectrometry assay in cycles 1 and 2.. Thirteen patients were enrolled, four in cohort I and nine in cohort II. All patients were assessable for toxicity and pharmacokinetic analysis. The grade and rate of toxicities were similar in both groups, and patients with elevation of bilirubin and/or transaminases did not require dose reduction of gemcitabine. Pharmacokinetic analysis revealed a reduction of the experimental area under the plasma concentration-time curve for gemcitabine and dFdU in patients with hepatic dysfunction when compared with patients with normal hepatic function. All other pharmacokinetic parameters were similar in the two cohorts. No statistical difference was demonstrated for all parameters evaluated between cycle 1 and cycle 2 in the two groups.. Gemcitabine 1000 mg/m2 can be administered as an FDR infusion in patients with altered hepatic function without causing additional toxicity compared with patients with normal hepatic function.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Area Under Curve; Biliary Tract Neoplasms; Chromatography, High Pressure Liquid; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Floxuridine; Gemcitabine; Humans; Infusions, Intravenous; Liver Diseases; Liver Function Tests; Male; Middle Aged; Pancreatic Neoplasms; Prospective Studies; Tandem Mass Spectrometry

Gemcitabine (dFdC) is a prodrug that undergoes metabolism by cytidine deaminase to form an inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU). The pharmacokinetics of dFdC and dFdU have been studied; however, their disposition has never been evaluated in a patient with ascites. A patient with pancreatic cancer and malignant ascites was treated with dFdC 1,500 mg/m2 over 150 minutes weekly for 3 weeks, repeated every 4 weeks. Serial plasma and ascites samples were obtained on weeks 1 and 2 of cycle 2. High-pressure liquid chromatography was used to quantify dFdC and dFdU in plasma and ascites. The systemic dispositions of dFdC and dFdU were similar to those reported in patients without ascites. The concentration of dFdC in ascites approached 1 mg/ml. Ascitic fluid did not serve as a depot for dFdC, and the agent's concentration in ascites approached that at which its phosphorylation is saturated.

Topics: Abdominal Pain; Adenocarcinoma; Antimetabolites, Antineoplastic; Ascites; Catheters, Indwelling; Chromatography, High Pressure Liquid; Deoxycytidine; Female; Floxuridine; Fluorouracil; Gemcitabine; Humans; Middle Aged; Pancreatic Neoplasms; Urinary Tract Infections