ABCG2 modulates chlorothiazide permeability--in vitro-characterization of its interactions.
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.
Solvo Biotechnology, Szeged, Hungary.
Erzsébet
E
Beéry
Zsuzsanna
Z
Rajnai
Tibor
T
Abonyi
Ildikó
I
Makai
Száva
S
Bánsághi
Franciska
F
Erdő
István
I
Sziráki
Krisztina
K
Herédi-Szabó
Emese
E
Kis
Márton
M
Jani
János
J
Márki-Zay
Gábor K
GK
Tóth
Péter
P
Krajcsi
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D002740:Chlorothiazide / Q000378:metabolism*; D004232:Diuretics / Q000378:metabolism*; D004285:Dogs; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism*; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007700:Kinetics; D061985:Madin Darby Canine Kidney Cells; D049990:Membrane Transport Modulators / Q000494:pharmacology; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D049993:Sodium Chloride Symporter Inhibitors / Q000378:metabolism*; D022161:Transport Vesicles / Q000187:drug effects / Q000378:metabolism
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D002740:Chlorothiazide; D004232:Diuretics; D004970:Estrone; D049990:Membrane Transport Modulators; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D049993:Sodium Chloride Symporter Inhibitors; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; C017296:estrone sulfate