2--2--difluoro-2--deoxyuridine and Lung-Neoplasms

To study the impact of the 79A>C polymorphism in the cytidine deaminase (CDA) gene on the pharmacokinetics of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) in non-small-cell lung cancer (NSCLC) patients.. Patients (n = 20) received gemcitabine 1,125 mg/m(2) as a 30 min i.v. infusion as part of treatment for NSCLC. Plasma samples were collected during 0-6 h after gemcitabine administration. Gemcitabine and dFdU were quantified by high performance liquid chromatography with ultraviolet detection. The CDA 79A>C genotype was determined with PCR and DNA sequencing.. Gemcitabine was rapidly cleared from plasma and undetectable after 3 h. The allele frequency of the 79A>C polymorphism was 0.40. Diplotypes were distributed as A/A n = 8, A/C n = 8 ,and C/C n = 4. No significant differences were found between the different CDA genotypes and gemcitabine or dFdU AUC, clearance, or half-life.. The 79A>C polymorphism in the CDA gene does not have a major consistent and signficant impact on gemcitabine pharmacokinetics.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cytidine Deaminase; Deoxycytidine; Female; Floxuridine; Gemcitabine; Gene Frequency; Genotype; Humans; Lung Neoplasms; Male; Metabolic Clearance Rate; Middle Aged; Polymorphism, Single Nucleotide

Gemcitabine, 2',2'-difluoro-2'-deoxycytidine (dFdC) is a pyrimidine antimetabolite employed against several human malignancies. It undergoes intracellular activation to the pharmacologically active triphosphate form (dFdCTP) and metabolic inactivation to the metabolite 2',2'-difluorodeoxyuridine (dFdU). In order to investigate the human plasma pharmacokinetics of dFdC and dFdU, we developed and validated an HPLC-MS/MS method, adding 2'-deoxycytidine as internal standard and simply precipitating the protein with acetonitrile. The method requires a small sample (125 microl), and it is rapid and selective, allowing good resolution of peaks from the plasma matrix in only 7 min. It is sensitive, precise and accurate, with overall precision, expressed as CV%, always less than 10.0% for both analytes and high recovery: > or = 80%. The limits of detection for dFdC and dFdU were 0.1 and 1.1 ng/ml, but considering the high concentrations in the plasma of patients investigated, we set the limit of quantitation at 20 ng/ml (0.08 microM) for dFdC and 250 ng/ml for dFdU, and validated the assay up to the dFdC concentration of 6.0 microg/ml (22.8 microM). The method was successfully used to study the drug pharmacokinetics in patients with advanced non-small-cell lung cancer in a phase II trial with gemcitabine administered as a fixed dose-rate infusion.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Chromatography, High Pressure Liquid; Cisplatin; Deoxycytidine; Floxuridine; Gemcitabine; Humans; Lung Neoplasms; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

We investigated the pharmacokinetics of gemcitabine and its metabolite in two male patients (52 and 56-year-old) with advanced urothelial cancer receiving hemodialysis three times a week.. Gemcitabine, 1000 mg/m(2) in 100 ml of saline, was intravenously administered for 30 min. The concentration of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) was measured at several given time points using a high-pressure liquid chromatography assay. Pharmacokinetic parameters were determined using the two-compartment modeling program.. Gemcitabine was rapidly eliminated from plasma even in patients with renal dysfunction. No obvious differences in pharmacokinetic parameters such as the t(1/2), AUC and C(max) of gemcitabine were observed between the patients on hemodialysis and those with normal renal function in previous reports. On the other hand, dFdU showed a sustained level until hemodialysis was initiated. Hemodialysis could reduce the plasma dFdU level by approximately 50%.. According to the previous information, no dose modification of gemcitabine may be required for patients with renal impairment or hemodialysis. However, gemcitabine should be given with caution because only limited information is available, and the clinical effect of sustained and/or accumulated dFdU is unknown.

Topics: Antimetabolites, Antineoplastic; Area Under Curve; Bone Neoplasms; Cystectomy; Deoxycytidine; Fatal Outcome; Floxuridine; Gemcitabine; Humans; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Renal Dialysis; Renal Insufficiency; Ureteral Neoplasms; Urinary Bladder Neoplasms