Document Detail

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).
MedLine Citation:
PMID:  18981587     Owner:  NLM     Status:  MEDLINE    
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.
Ken-ichi Fujita; Fumio Nagashima; Wataru Yamamoto; Hisashi Endo; Yu Sunakawa; Keishi Yamashita; Hiroo Ishida; Keiko Mizuno; Mototsugu Matsunaga; Kazuhiro Araki; Ryuhei Tanaka; Wataru Ichikawa; Toshimichi Miya; Masaru Narabayashi; Yuko Akiyama; Kaori Kawara; Yuichi Ando; Yasutsuna Sasaki
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Publication Detail:
Type:  Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biological & pharmaceutical bulletin     Volume:  31     ISSN:  0918-6158     ISO Abbreviation:  Biol. Pharm. Bull.     Publication Date:  2008 Nov 
Date Detail:
Created Date:  2008-11-04     Completed Date:  2009-01-05     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9311984     Medline TA:  Biol Pharm Bull     Country:  Japan    
Other Details:
Languages:  eng     Pagination:  2137-42     Citation Subset:  IM    
Department of Medical Oncology, Saitama International Medical Center-Comprehensive Cancer Center, Saitama Medical University, Saitama, Japan.
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MeSH Terms
Antineoplastic Combined Chemotherapy Protocols / administration & dosage,  adverse effects,  pharmacokinetics*,  therapeutic use
Camptothecin / administration & dosage,  adverse effects,  analogs & derivatives,  pharmacokinetics,  therapeutic use
Colorectal Neoplasms* / drug therapy,  genetics,  pathology
Drug Administration Schedule
Fluorouracil / administration & dosage,  adverse effects,  pharmacokinetics,  therapeutic use
Infusions, Intravenous
Leucovorin / administration & dosage,  adverse effects,  pharmacokinetics,  therapeutic use
Linkage Disequilibrium
Metabolic Detoxication, Drug
Middle Aged
Multidrug Resistance-Associated Proteins / genetics*
Neoplasm Metastasis
Polymorphism, Single Nucleotide*
Reg. No./Substance:
0/IFL protocol; 0/Multidrug Resistance-Associated Proteins; 0/multidrug resistance-associated protein 2; 100286-90-6/irinotecan; 51-21-8/Fluorouracil; 58-05-9/Leucovorin; 7689-03-4/Camptothecin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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