Comparison of the inhibitory properties of the fruit component naringenin and its glycosides against OATP1A2 genetic variants

Naoya Araki; Tokio Morita; Takeshi Akiyoshi; Hiroki Kataoka; Kodai Yajima; Kazuhiro Katayama; Ayuko Imaoka; Hisakazu Ohtani

doi:10.1016/j.dmpk.2022.100464

Comparison of the inhibitory properties of the fruit component naringenin and its glycosides against OATP1A2 genetic variants

Drug Metab Pharmacokinet. 2022 Oct:46:100464. doi: 10.1016/j.dmpk.2022.100464. Epub 2022 May 10.

Authors

Naoya Araki¹, Tokio Morita², Takeshi Akiyoshi³, Hiroki Kataoka⁴, Kodai Yajima⁵, Kazuhiro Katayama⁶, Ayuko Imaoka⁷, Hisakazu Ohtani⁸

Affiliations

¹ Division of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. Electronic address: naoya-araki-708@keio.jp.
² Division of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. Electronic address: morita.tokio@keio.jp.
³ Division of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan; Department of Clinical Pharmacy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. Electronic address: akiyoshi-tk@pha.keio.ac.jp.
⁴ Division of Clinical Pharmacokinetics, 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 Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. Electronic address: kodai.ss-kp8181@keio.jp.
⁶ 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.
⁷ Division of Clinical Pharmacokinetics, 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 Division of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan; Department of Clinical Pharmacy, 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: 35841754
DOI: 10.1016/j.dmpk.2022.100464

Abstract

Non-synonymous genetic variants of organic anion-transporting polypeptide (OATP) 1A2 with altered transport activity have been identified. Naringin and narirutin, which are found in grapefruit, and their aglycon naringenin inhibit OATP1A2. However, their inhibitory effects on OATP1A2 variants have not been investigated, nor has the influence of their molecular structure, such as the number of sugar moieties, on their inhibitory potency. This study aimed to investigate the inhibitory effects of naringenin, its monosaccharide glycoside prunin, and its disaccharide glycosides naringin and narirutin on fexofenadine (FEX) uptake by OATP1A2 variants (Ile13Thr, Asn128Tyr, Ala187Thr, and Thr668Ser). Naringin, narirutin, and prunin inhibited FEX (0.3 μM) uptake by all of the examined OATP1A2 variants in a concentration-dependent manner. Compared with those for the wild type, the inhibition constants (K_i) of naringin, narirutin, and prunin for the Ala187Thr variant were significantly increased by 3.36-fold, 7.55-fold, and 10.6-fold, respectively. Naringenin inhibited all of the OATP1A2 variants, except Ala187Thr, concentration-dependently. The order of inhibitory potency was as follows for all variants: aglycone > monosaccharide glycoside > disaccharide glycosides. These results suggest that the Ala187Thr variant is less vulnerable to inhibition by naringenin and its glycosides. Moreover, greater glycosylation of naringenin reduces its inhibitory potency against OATP1A2.

Keywords: Citrus fruits; Food-drug interaction; Genetic variants; Naringenin; Naringin; Narirutin; OATP1A2; Prunin.

MeSH terms

Anions
Disaccharides
Flavanones* / pharmacology
Fruit
Glycosides / pharmacology
Monosaccharides
Organic Anion Transporters* / genetics
Peptides

Substances

naringenin
Glycosides
Flavanones
fexofenadine
Organic Anion Transporters
Disaccharides
Peptides
Monosaccharides
Anions