Influence of drug-transporter polymorphisms on the pharmacokinetics of fexofenadine enantiomers.

Abstract

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.

• Authors: Yumiko Akamine, Masatomo Miura, Satoko Sunagawa, Hideaki Kagaya, Norio Yasui-Furukori, Tsukasa Uno
• Journal: Xenobiotica; the fate of foreign compounds in biological systems (Xenobiotica) Vol. 40 Issue 11 Pg. 782-9 (Nov 2010) ISSN: 1366-5928 [Electronic] England
• PMID: 20839930 (Publication Type: Journal Article)

Chemical References

• ABCB1 protein, human
• ABCC2 protein, human
• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Anti-Allergic Agents
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• Neoplasm Proteins
• Terfenadine
• fexofenadine

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (genetics)
• Adult
• Anti-Allergic Agents (chemistry, pharmacokinetics)
• Female
• Humans
• Male
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (genetics)
• Neoplasm Proteins (genetics)
• Polymorphism, Genetic
• Stereoisomerism
• Terfenadine (analogs & derivatives, chemistry, pharmacokinetics)
• Young Adult