Pharmacokinetics of gemcitabine in non-small-cell lung cancer patients: impact of the 79A>C cytidine deaminase polymorphism.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
The 79A>C polymorphism in the CDA gene does not have a major consistent and signficant impact on gemcitabine pharmacokinetics.
Maring
Jan Gerard
JG
Department of Pharmacy, Diaconessen Hospital Meppel & Bethesda Hospital Hoogeveen, Hoogeveenseweg 38, 7943 KA, Meppel, The Netherlands. maring@noorderboog.nl
Wachters
Floris M
FM
Slijfer
Monique
M
Maurer
J Marina
JM
Boezen
H Marike
HM
Uges
Donald R A
DR
de Vries
Elisabeth G E
EG
Groen
Harry J M
HJ
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood* / Q000188:drug therapy; D003564:Cytidine Deaminase / Q000235:genetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D005467:Floxuridine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood* / Q000188:drug therapy; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D005467:Floxuridine; D003841:Deoxycytidine; D003564:Cytidine Deaminase; C084565:2',2'-difluoro-2'-deoxyuridine; D000093542:Gemcitabine