Comparison of the transport kinetics of fexofenadine and its pH dependency among OATP1A2 genetic variants

Hongye Han; Takeshi Akiyoshi; Tokio Morita; Hiroki Kataoka; Kazuhiro Katayama; Kodai Yajima; Ayuko Imaoka; Hisakazu Ohtani

doi:10.1016/j.dmpk.2022.100470

Comparison of the transport kinetics of fexofenadine and its pH dependency among OATP1A2 genetic variants

Drug Metab Pharmacokinet. 2022 Dec:47:100470. doi: 10.1016/j.dmpk.2022.100470. Epub 2022 Aug 22.

Authors

Hongye Han¹, Takeshi Akiyoshi², Tokio Morita³, Hiroki Kataoka⁴, Kazuhiro Katayama⁵, Kodai Yajima⁶, Ayuko Imaoka⁷, Hisakazu Ohtani⁸

Affiliations

¹ Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. Electronic address: hanhongye1995@keio.jp.
² Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan; Keio University School of Medicine, 35, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. Electronic address: akiyoshi-tk@pha.keio.ac.jp.
³ Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. Electronic address: morita.tokio@keio.jp.
⁴ Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. Electronic address: kataoka-hrk@keio.jp.
⁵ Division of Molecular Targeting Therapeutics, School of Pharmacy, Nihon University, 7-7-1, Narashinodai, Funabashi-shi, Chiba, 274-8555, Japan. Electronic address: katayama.kazuhiro@nihon-u.ac.jp.
⁶ Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. Electronic address: kodai.ss-kp8181@keio.jp.
⁷ Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. Electronic address: imaoka-ay@pha.keio.ac.jp.
⁸ Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan; Keio University School of Medicine, 35, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan; Department of Pharmacy, Keio University Hospital, 35, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. Electronic address: ohtani-tky@umin.net.

PMID: 36116173
DOI: 10.1016/j.dmpk.2022.100470

Abstract

Little is known about the influence of non-synonymous genetic variations in the organic anion-transporting polypeptide (OATP) 1A2 on the transport kinetics of its substrate fexofenadine. Moreover, the pH-dependency of fexofenadine uptake also remains unclear. This study aimed to evaluate the effects of genetic variants (Ile13Thr, Asn128Tyr, Glu172Asp, Ala187Thr, and Thr668Ser) on the OATP1A2-mediated uptake of fexofenadine at pH 6.3 and 7.4 and compare the pH dependency of OATP1A2-mediated uptake of fexofenadine and estrone 3-sulfate. The uptake clearances of 0.3 μM and 300 μM fexofenadine were compared with those of 0.3 μM and 300 μM estrone 3-sulfate at pH 6.3 and 7.4. Among the six variants examined, the Thr668Ser variant showed the highest fexofenadine uptake clearance (V_max/K_m); i.e., 4.53- and 6.28-fold higher uptake clearance than the wild type at pH 6.3 and 7.4, respectively. All variants exhibited significantly higher fexofenadine uptake at pH 6.3 than at pH 7.4. Compared with estrone 3-sulfate uptake, the uptake of 0.3 μM fexofenadine was less sensitive to pH. Our findings suggest that genetic variations in OATP1A2 may lead to altered intestinal absorption of fexofenadine, such as increased absorption in subjects bearing the Thr668Ser variant, which showed higher uptake activity.

Keywords: Amino acid substitution; Estrone 3-sulfate; Intestinal absorption; Organic anion-transporting polypeptide 1A2; Single nucleotide polymorphism; pH-dependent uptake.

MeSH terms

Estrone*
Humans
Hydrogen-Ion Concentration
Organic Anion Transporters* / genetics
Sulfates
Terfenadine

Substances

fexofenadine
Estrone
Terfenadine
Organic Anion Transporters
Sulfates