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

CímABCG2 modulates chlorothiazide permeability--in vitro-characterization of its interactions.
Publication TypeJournal Article
Year of Publication2012
AuthorsBeeéry E, Rajnai Z, Abonyi T, Makai I, Bánsághi S, Erdő F, Sziráki I, Herédi-Szabó K, Kis E, Jani M, Márki-Zay J, K. GTóth, Krajcsi P
JournalDrug Metabolism and Pharmacokinetics
Volume27
Start Page349
Issue3
KulcsszavakABCG2 substrate, absorption, Caco-2, chlorothiazide, MDCKII-BCRP, probe for regulatory studies, vesicular transport
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.

Webcímhttp://www.ncbi.nlm.nih.gov/pubmed/22790065