Association of ATP-binding cassette, sub-family C, number 2 (ABCC2) genotype with pharmacokinetics of irinotecan in Japanese patients with metastatic colorectal cancer treated with irinotecan plus infusional 5-fluorouracil/leucovorin (FOLFIRI).
ATP-binding cassette, sub-family C, number 2 (ABCC2) is involved in the biliary excretion of irinotecan and its metabolites, SN-38 and SN-38 glucuronide. Effects of the ABCC2 genotype on the pharmacokinetics (PK) of irinotecan and the metabolites were examined in Japanese patients with metastatic colorectal cancer receiving irinotecan plus infusional 5-fluorouracil/leucovorin (FOLFIRI). ABCC2 genotypes (-1549G>A, -1023G>A, -1019A>G, -24C>T, 1249G>A and 3972C>T) and haplotypes were analyzed for 67 patients with cancer. PK was also examined in a subset of 31 patients receiving FOLFIRI. Relationship between the ABCC2 genotypes or diplotypes and area under the time-concentration curve (AUC) of irinotecan and the metabolites normalized by irinotecan dose was analyzed. The lower AUC of irinotecan was seen in patients with A/A or G/A genotypes at 1249 of the ABCC2 gene than others (p=0.011, Mann-Whitney U teat). AUC of SN-38 in patients with A/A or G/A genotypes at -1023 was significantly lower than that in others (p=0.018). The haplotype I included -1023A (GAACGC) was the most frequent one with the allele frequency of 0.366. The AUC of SN-38 observed in patients with diplotypes harboring at least one haplotype I was lower than that observed in others (p=0.023). The haplotype IV consisted of 1249 (GGACAC) and was the fourth most frequent one with the allele frequency of 0.127. Patients with diplotypes carrying at least one haplotype IV showed lower AUC of irinotecan than others (p=0.011). Thus, ABCC2 genotype is one of the predictors of the variability of irinotecan PK in Japanese patients with metastatic colorectal cancer receiving FOLFIRI.
Fujita
Ken-ichi
K
Department of Medical Oncology, Saitama International Medical Center-Comprehensive Cancer Center, Saitama Medical University, Saitama, Japan. fujitak@saitama-med.ac.jp
Nagashima
Fumio
F
Yamamoto
Wataru
W
Endo
Hisashi
H
Sunakawa
Yu
Y
Yamashita
Keishi
K
Ishida
Hiroo
H
Mizuno
Keiko
K
Matsunaga
Mototsugu
M
Araki
Kazuhiro
K
Tanaka
Ryuhei
R
Ichikawa
Wataru
W
Miya
Toshimichi
T
Narabayashi
Masaru
M
Akiyama
Yuko
Y
Kawara
Kaori
K
Ando
Yuichi
Y
Sasaki
Yasutsuna
Y
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008658:Inactivation, Metabolic; D007262:Infusions, Intravenous; D000077146:Irinotecan; D007564:Japan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide
D002166:Camptothecin; D005472:Fluorouracil; D000077146:Irinotecan; D002955:Leucovorin; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human