Additive effects of drug transporter genetic polymorphisms on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients.
OBJECTIVE
Effects of genetic polymorphisms/variations of ABCB1, ABCC2, ABCG2 and SLCO1B1 in addition to "UGT1A1*28 or *6" on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients were investigated.


METHODS
Associations between transporter haplotypes/variations along with UGT1A1*28 or *6 and SN-38 area under the time-concentration curve (AUC) or neutropenia were examined in irinotecan monotherapy (55 patients) and irinotecan-cisplatin-combination therapy (62 patients).


RESULTS
Higher SN-38 AUC values were observed in ABCB1 2677G>T (A893S) (*2 group) for both regimens. Associations of grade 3/4 neutropenia were observed with ABCC2 -1774delG (*1A), ABCG2 421C>A (Q141K) and IVS12 + 49G>T ((#) IIB) and SLCO1B1 521T>C (V174A) (*15 x 17) in the irinotecan monotherapy, while they were evident only in homozygotes of ABCB1*2, ABCG2 (#) IIB, SLCO1B1*15 x 17 in the cisplatin-combination therapy. With combinations of haplotypes/variations of two or more genes, neutropenia incidence increased, but their prediction power for grade 3/4 neutropenia is still unsatisfactory.


CONCLUSIONS
Certain transporter genotypes additively increased irinotecan-induced neutropenia, but their clinical importance should be further elucidated.
Sai
Kimie
K
Division of Functional Biochemistry and Genomics, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. sai@nihs.go.jp
Saito
Yoshiro
Y
Maekawa
Keiko
K
Kim
Su-Ryang
SR
Kaniwa
Nahoko
N
Nishimaki-Mogami
Tomoko
T
Sawada
Jun-ichi
J
Shirao
Kuniaki
K
Hamaguchi
Tetsuya
T
Yamamoto
Noboru
N
Kunitoh
Hideo
H
Ohe
Yuichiro
Y
Yamada
Yasuhide
Y
Tamura
Tomohide
T
Yoshida
Teruhiko
T
Matsumura
Yasuhiro
Y
Ohtsu
Atsushi
A
Saijo
Nagahiro
N
Minami
Hironobu
H
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D044466:Asian People / Q000235:genetics; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D000077146:Irinotecan; D000089762:Multidrug Resistance-Associated Protein 2; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D009503:Neutropenia / Q000139:chemically induced / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D002945:Cisplatin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000089762:Multidrug Resistance-Associated Protein 2; D027361:Organic Anion Transporters; D000099148:UGT1A1 Enzyme; C000715087:ABCC2 protein, human