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  • ABCG2 modulates chlorothiazide permeability--in vitro-characterization of its interactions.

ABCG2 modulates chlorothiazide permeability--in vitro-characterization of its interactions.

Drug metabolism and pharmacokinetics (2012-07-14)
Erzsébet Beéry, Zsuzsanna Rajnai, Tibor Abonyi, Ildikó Makai, Száva Bánsághi, Franciska Erdő, István Sziráki, Krisztina Herédi-Szabó, Emese Kis, Márton Jani, János Márki-Zay, Gábor K Tóth, Péter Krajcsi
ABSTRACT

We are showing that chlorothiazide, a diuretic, is an ABCG2 substrate. It is a Biopharmaceutics Classification System/Biopharmaceutics Drug Distribution and Classification System (BCS/BDDCS) Class IV drug with low bioavailability. Therefore, we tested if chlorothiazide interacts with major apically located intestinal efflux transporters. Our data show that chlorothiazide is transported by ABCG2 with a Km value of 334.6 µM and does not interact with ABCB1 or ABCC2. The chlorothiazide-ABCG2 interaction results in a vectorial transport in MDCKII-BCRP and Caco-2 cells with efflux ratios of 36 and 8.1 respectively. Inhibition of ABCG2 in Caco-2 cells reduced the efflux ratio to 1.4, suggesting that ABCG2 plays a role in limiting chlorothiazide bioavailability in humans.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Estrone 3-sulfate sodium salt, contains ~35% Tris as stabilizer
Sigma-Aldrich
Chlorothiazide, thiazide diuretic
Supelco
Chlorothiazide, Pharmaceutical Secondary Standard; Certified Reference Material
Chlorothiazide, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Estrone 3-sulfate potassium salt, ≥98%
Sigma-Aldrich
SB-BCRP-M-PREDEASY-ATPase kit, membrane based kit for Human BCRP ATPase Transport Assays
Sigma-Aldrich
SB-BCRP-HEK293