Influence of drug-transporter polymorphisms on the pharmacokinetics of fexofenadine enantiomers.
This study investigated an association of SLCO (encoding organic anion-transporting polypeptides (OATP), 1B1, 1B3, and 2B1), ABCB1 (P-glycoprotein (P-gp)), ABCC2 multidrug resistance protein 2 (MRP2), and ABCG2 (breast cancer resistance protein (BCRP)) polymorphisms with fexofenadine enantiomer pharmacokinetics after an oral dose of fexofenadine (60 mg) in 24 healthy subjects. The area under the plasma concentration-time curve (AUC(0-24)) of S-fexofenadine, but not R-fexofenadine, was significantly lower in subjects with a SLCO2B1*1/*1 allele as compared to subjects with a *3 allele (p = 0.031). The AUC(0-24) of S-fexofenadine was significantly lower in subjects with a wild-type combination of SLCO2B1*1/*1/ABCB1 1236CC, SLCO2B1*1/*1/ABCB1 3435CC, SLCO2B1*1/*1/ABCC2 -24CC, and ABCB1 1236CC/3435CC/ABCC2 -24CC compared to other polymorphic genotypes (p = 0.010, 0.033, 0.022, and 0.036, respectively), whereas there was no difference in the AUC(0-24) between the SLCO1B1/1B3 plus ABCB1 and ABCC2 groups. The pharmacokinetic properties of S-fexofenadine are affected by a single polymorphism of SLCO2B1 in combination with several polymorphisms of ABCB1 C1236T, C3435T, and ABCC2 C-24T. However, the ABCG2 polymorphism was not associated with fexofenadine pharmacokinetics. These findings suggest that a combination of multiple transporters, including OATP, P-gp, and MRP2, reacts strongly to fexofenadine exposure in the small intestine and liver, resulting in different dispositions of both enantiomers.
Akamine
Yumiko
Y
Department of Hospital Pharmacy, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
Miura
Masatomo
M
Sunagawa
Satoko
S
Kagaya
Hideaki
H
Yasui-Furukori
Norio
N
Uno
Tsukasa
T
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D018926:Anti-Allergic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D013237:Stereoisomerism; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D055815:Young Adult
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D018926:Anti-Allergic Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D016593:Terfenadine; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C093230:fexofenadine