Accéder au contenu
MilliporeSigma

Substrate- and dose-dependent drug interactions with grapefruit juice caused by multiple binding sites on OATP2B1.

Pharmaceutical research (2014-02-20)
Yoshiyuki Shirasaka, Takanori Mori, Yukiko Murata, Takeo Nakanishi, Ikumi Tamai
RÉSUMÉ

OATP2B1-mediated grapefruit juice (GFJ)-drug interactions are substrate-dependent; for example, GFJ ingestion significantly reduces bioavailability of fexofenadine, but not pravastatin. In the present study, we aimed to establish whether this observation can be explained by the presence of multiple binding sites (MBS) on OATP2B1. OATP2B1-mediated drug uptake was evaluated using a Xenopus oocyte expression system. Drug concentration was quantified by LC/MS/MS analysis. OATP2B1-mediated uptake of pravastatin and fexofenadine exhibited biphasic saturation kinetics, indicating the presence of MBS on OATP2B1. GFJ strongly inhibited pravastatin uptake mediated by the high-affinity site on OATP2B1, while no significant inhibition of the low-affinity site was observed. In contrast, high-affinity transport of fexofenadine was only modestly inhibited by GFJ, while significant inhibition of the low-affinity site was observed. Contribution analysis indicated that both drugs are transported via the low-affinity site on OATP2B1 at therapeutically relevant concentrations. These findings indicate that only fexofenadine is expected to interact with GFJ on OATP2B1 at therapeutic concentrations, in accordance with the clinical observations. Substrate- and dose-dependent GFJ-drug interactions mediated by OATP2B1 might be explained in terms of the presence of MBS: interaction occurs only when drug and GFJ components share the same binding site on OATP2B1.

MATÉRIAUX
Référence du produit
Marque
Description du produit

Sigma-Aldrich
Bicarbonate de sodium, ACS reagent, ≥99.7%
Sigma-Aldrich
Bicarbonate de sodium, powder, BioReagent, for molecular biology, suitable for cell culture, suitable for insect cell culture
Sigma-Aldrich
Chlorure de sodium, for molecular biology, DNase, RNase, and protease, none detected, ≥99% (titration)
Sigma-Aldrich
Bicarbonate de sodium, ReagentPlus®, ≥99.5%, powder
Sigma-Aldrich
Chlorure de sodium solution, 5 M in H2O, BioReagent, for molecular biology, suitable for cell culture
Sigma-Aldrich
Chlorure de sodium solution, 0.9% in water, BioXtra, suitable for cell culture
Sigma-Aldrich
Chlorure de sodium, BioReagent, suitable for cell culture, suitable for insect cell culture, suitable for plant cell culture, ≥99%
Sigma-Aldrich
Bicarbonate de sodium, anhydrous, free-flowing, Redi-Dri, ACS reagent, ≥99.7%
SAFC
Chlorure de sodium solution, 5 M
Sigma-Aldrich
Chlorure de sodium, BioXtra, ≥99.5% (AT)
Sigma-Aldrich
Chlorure de sodium solution, BioUltra, for molecular biology, ~5 M in H2O
Sigma-Aldrich
Chlorure de sodium, BioUltra, for molecular biology, ≥99.5% (AT)
Sigma-Aldrich
Chlorure de sodium, 99.999% trace metals basis
Sigma-Aldrich
Bicarbonate de sodium, puriss., meets analytical specification of Ph. Eur., BP, USP, FCC, E500, 99.0-100.5%, powder
Sigma-Aldrich
Chlorure de sodium solution, 5 M
Sigma-Aldrich
Chlorure de sodium, meets analytical specification of Ph. Eur., BP, USP, 99.0-100.5%
Sigma-Aldrich
Bicarbonate de sodium, BioXtra, 99.5-100.5%
Sigma-Aldrich
Naringin, ≥95% (HPLC)
USP
Bicarbonate de sodium, United States Pharmacopeia (USP) Reference Standard
Supelco
Chlorure de sodium, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Bicarbonate de sodium, anhydrous, free-flowing, Redi-Dri, ReagentPlus®, ≥99.5%
Sigma-Aldrich
Chlorure de sodium, BioPerformance Certified, ≥99% (titration), suitable for insect cell culture, suitable for plant cell culture
Sigma-Aldrich
Naringin, ≥90% (HPLC), from citrus fruit