Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan.
We performed comprehensive haplotyping of ABCB1/MDR1 gene blocks using 49 genetic polymorphisms, including seven novel ones, obtained from 145 Japanese subjects. The ABCB1/MDR1 gene was divided into four blocks (Blocks -1, 1, 2, and 3) based on linkage disequilibrium analysis of polymorphisms. Using an expectation-maximization based program, 1, 2, 8, and 3 haplotype groups (3, 12, 32, and 18 haplotypes) were identified in Blocks -1, 1, 2, and 3, respectively. Within Block 2, haplotype groups *1, *2, *4, *6, and *8 reported by Kim and colleagues (Clin Pharmacol Ther 2001; 70:189-199) were found, and additional three groups (*9 to *11) were newly defined. We analyzed the association of haplotypes with the renal clearance of irinotecan and its metabolites in 49 Japanese cancer patients given irinotecan intravenously. There was a significant association of the *2 haplotype in Block 2, which includes 1236C>T, 2677G>T and 3435C>T, with a reduced renal clearance of those compounds. Moreover, tendencies of reduced and increased renal clearance were also observed with *1f in Block 2 and *1b in Block 3, respectively. These findings suggest that the P-glycoprotein encoded by ABCB1/MDR1 in the proximal tubules plays a substantial role in renal exclusion of drugs and, moreover, that block-haplotyping is valuable for pharmacogenetic studies.
Sai
Kimie
K
Project Team for Pharmacogenetics, Division of Xenobiotic Metabolism and Disposition, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. sai@nihg.go.jp
Kaniwa
Nahoko
N
Itoda
Masaya
M
Saito
Yoshiro
Y
Hasegawa
Ryuichi
R
Komamura
Kazuo
K
Ueno
Kazuyuki
K
Kamakura
Shiro
S
Kitakaze
Masafumi
M
Shirao
Kuniaki
K
Minami
Hironobu
H
Ohtsu
Atsushi
A
Yoshida
Teruhiko
T
Saijo
Nagahiro
N
Kitamura
Yutaka
Y
Kamatani
Naoyuki
N
Ozawa
Shogo
S
Sawada
Jun-Ichi
J
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001483:Base Sequence; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D017931:DNA Primers; D019450:Genes, MDR; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D000077146:Irinotecan; D007564:Japan; D007668:Kidney / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D000077146:Irinotecan; D002166:Camptothecin