Drug Metabolism and Pharmacokinetics 2012-01-01

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

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

Index: Drug Metab. Pharmacokinet. 27(3) , 349-53, (2012)

Full Text: HTML

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.