Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism.
OBJECTIVE
Gemcitabine is rapidly metabolized to its inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU), by cytidine deaminase (CDA). We previously reported that a patient with homozygous 208A alleles of CDA showed severe adverse reactions with an increase in gemcitabine plasma level. This study extended the investigation of the effects of CDA genetic polymorphisms on gemcitabine pharmacokinetics and toxicities.


METHODS
Genotyping of CDA was performed by a direct sequencing of DNA obtained from the peripheral blood of Japanese gemcitabine-naïve cancer patients (n = 256). The patients recruited to the association study received a 30-minute intravenous infusion of gemcitabine at a dose of either 800 or 1,000 mg/m2, and eight blood samples were periodically collected (n = 250). Plasma levels of gemcitabine and dFdU were measured by high-performance liquid chromatography. Plasma CDA activities toward cytidine and gemcitabine were also measured (n = 121).


RESULTS
Twenty-six genetic variations, including 14 novel ones and two known nonsynonymous single nucleotide polymorphisms (SNPs), were detected. Haplotypes harboring the nonsynonymous SNPs 79A>C (Lys27Gln) and 208G>A (Ala70Thr) were designated *2 and *3, respectively. The allelic frequencies of the two SNPs were 0.207 and 0.037, respectively. Pharmacokinetic parameters of gemcitabine and plasma CDA activities significantly depended on the number of haplotype *3. Haplotype *3 was also associated with increased incidences of grade 3 or higher neutropenia in the patients who were coadministered fluorouracil, cisplatin, or carboplatin. Haplotype *2 showed no significant effect on gemcitabine pharmacokinetics.


CONCLUSIONS
Haplotype *3 harboring a nonsynonymous SNP, 208G>A (Ala70Thr), decreased clearance of gemcitabine, and increased incidences of neutropenia when patients were coadministered platinum-containing drugs or fluorouracil.
Sugiyama
Emiko
E
Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.
Kaniwa
Nahoko
N
Kim
Su-Ryang
SR
Kikura-Hanajiri
Ruri
R
Hasegawa
Ryuichi
R
Maekawa
Keiko
K
Saito
Yoshiro
Y
Ozawa
Shogo
S
Sawada
Jun-ichi
J
Kamatani
Naoyuki
N
Furuse
Junji
J
Ishii
Hiroshi
H
Yoshida
Teruhiko
T
Ueno
Hideki
H
Okusaka
Takuji
T
Saijo
Nagahiro
N
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics* / Q000633:toxicity; D003564:Cytidine Deaminase / Q000097:blood / Q000235:genetics*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D005260:Female; D005838:Genotype; D006801:Humans; D007262:Infusions, Intravenous; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D000093542:Gemcitabine