Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure.
It has been reported that organic anion-transporting polypeptide (OATP) 1B1, OATP1B3 and multidrug resistance-associated protein 2 are involved in the hepatobiliary transport of olmesartan. We investigated the association of SLCO1B1, SLCO1B3 and ABCC2 polymorphisms with the pharmacokinetics of olmesartan. We sequenced all exons, exon-intron junctions and the 5' and 3' flanking regions of the three genes in 115 individuals from African-American, Hispanic and Caucasian populations who had participated in our clinical studies. A total of 348 single-nucleotide polymorphisms (SNPs) were identified with a minor allele frequency of ≥0.01 in at least one population; 132 SNPs were detected in SLCO1B1, 130 in SLCO1B3 and 86 in ABCC2. We characterized the linkage disequilibrium (LD) and haplotypes shared across the populations and then evaluated the association between the haplotypes and the pharmacokinetics of olmesartan. Seven inter-ethnic LD blocks were observed in SLCO1B1, while three in SLCO1B3 and four in ABCC2. Although extensive variability in the sequences of SLCO1B1, SLCO1B3 and ABCC2 existed across the three populations, there was no remarkable difference in any pharmacokinetic parameters of olmesartan between subjects with and without any major haplotypes in the three transporter genes we tested.
Translational Medicine and Clinical Pharmacology Department, Daiichi Sankyo, Tokyo, Japan.
Seiko
S
Endo
Aiko
A
Fukahori
Shinya
S
Tokuhiro
Akira
A
Shinagawa
Joseph
J
Walker
Kazutaka
K
Yoshihara
Hitoshi
H
Ishizuka
Ichiro
I
Ieiri
Yuichi
Y
Sugiyama
D000328:Adult; D001741:Black or African American / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use; D015810:Linkage Disequilibrium; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D027361:Organic Anion Transporters / Q000235:genetics*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013777:Tetrazoles / Q000493:pharmacokinetics / Q000627:therapeutic use; D044465:White People / Q000235:genetics
D007093:Imidazoles; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013777:Tetrazoles; C000715087:ABCC2 protein, human; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C437965:olmesartan