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

Drug Metab Pharmacokinet. 2012;27(3):349-53. doi: 10.2133/dmpk.dmpk-11-nt-068. Epub 2011 Nov 29.

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 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
  • 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 Proteins
  • Neoplasm Proteins
  • Recombinant Proteins
  • Sodium Chloride Symporter Inhibitors
  • Estrone
  • multidrug resistance-associated protein 2
  • Chlorothiazide
  • Adenosine Triphosphate
  • estrone sulfate