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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP Binding Cassette Transporter, Subfamily B
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
-
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
-
ATP Binding Cassette Transporter, Subfamily G, Member 2
-
ATP-Binding Cassette Transporters / antagonists & inhibitors
-
ATP-Binding Cassette Transporters / genetics
-
ATP-Binding Cassette Transporters / metabolism*
-
Adenosine Triphosphate / antagonists & inhibitors
-
Adenosine Triphosphate / metabolism
-
Animals
-
Biological Transport / drug effects
-
Caco-2 Cells
-
Cell Membrane Permeability* / drug effects
-
Chlorothiazide / metabolism*
-
Diuretics / metabolism*
-
Dogs
-
Enterocytes / drug effects
-
Enterocytes / metabolism*
-
Estrone / analogs & derivatives
-
Estrone / metabolism
-
Humans
-
Intestinal Absorption / drug effects
-
Kinetics
-
Madin Darby Canine Kidney Cells
-
Membrane Transport Modulators / pharmacology
-
Multidrug Resistance-Associated Protein 2
-
Multidrug Resistance-Associated Proteins / genetics
-
Multidrug Resistance-Associated Proteins / metabolism
-
Neoplasm Proteins / antagonists & inhibitors
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism*
-
Recombinant Proteins / antagonists & inhibitors
-
Recombinant Proteins / metabolism
-
Sodium Chloride Symporter Inhibitors / metabolism*
-
Transport Vesicles / drug effects
-
Transport Vesicles / metabolism
Substances
-
ABCB1 protein, human
-
ABCC2 protein, human
-
ABCG2 protein, human
-
ATP Binding Cassette Transporter, Subfamily B
-
ATP Binding Cassette Transporter, Subfamily B, Member 1
-
ATP Binding Cassette Transporter, Subfamily G, Member 2
-
ATP-Binding Cassette Transporters
-
Diuretics
-
Membrane Transport Modulators
-
Multidrug Resistance-Associated Protein 2
-
Multidrug Resistance-Associated Proteins
-
Neoplasm Proteins
-
Recombinant Proteins
-
Sodium Chloride Symporter Inhibitors
-
Estrone
-
Chlorothiazide
-
Adenosine Triphosphate
-
estrone sulfate