Related Experiment Video
Updated: May 20, 2026
09:59
Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein
Published on: March 9, 2015
ABCG2 modulates chlorothiazide permeability--in vitro-characterization of its interactions
Erzsébet Beéry1, Zsuzsanna Rajnai, Tibor Abonyi
1Solvo Biotechnology, Szeged, Hungary.
Drug Metabolism and Pharmacokinetics
|July 14, 2012
Summary
Chlorothiazide, a diuretic, is transported by ABCG2, a key efflux transporter. This interaction limits the drug
Area of Science:
- Pharmacology
- Drug Transport
- Biopharmaceutics
Background:
- Chlorothiazide is a diuretic classified as a Biopharmaceutics Drug Distribution and Classification System (BCS/BDDCS) Class IV drug, indicating low bioavailability.
- Apically located intestinal efflux transporters play a crucial role in drug absorption and bioavailability.
Purpose of the Study:
- To investigate the interaction of chlorothiazide with major intestinal efflux transporters, specifically ABCG2, ABCB1, and ABCC2.
- To determine if ABCG2 contributes to the low bioavailability of chlorothiazide.
Main Methods:
- In vitro transport studies using cell lines (MDCKII-BCRP and Caco-2) expressing specific transporters.
- Assessing chlorothiazide transport kinetics (Km value) mediated by ABCG2.
- Evaluating the effect of ABCG2 inhibition on chlorothiazide efflux.
Main Results:
- Chlorothiazide is identified as a substrate of ABCG2, with a Michaelis constant (Km) of 334.6 µM.
- Chlorothiazide did not interact with ABCB1 or ABCC2 transporters.
- Significant vectorial transport of chlorothiazide by ABCG2 was observed in MDCKII-BCRP and Caco-2 cells (efflux ratios of 36 and 8.1, respectively).
- Inhibition of ABCG2 in Caco-2 cells decreased the efflux ratio to 1.4.
Conclusions:
- ABCG2 actively transports chlorothiazide.
- The interaction between chlorothiazide and ABCG2 is a significant factor limiting the drug's oral bioavailability in humans.
- Understanding this interaction may inform strategies to improve chlorothiazide efficacy.
Related Concept Videos
01:15Antihypertensive Drugs: Thiazide-Class Diuretics
Thiazide diuretics are sulfonamide derivatives featuring a benzothiadiazine ring system in their molecular structure. Based on this structure, thiazide diuretics can be categorized into two groups: thiazide-type and thiazide-like diuretics. Thiazide-type diuretics, including hydrochlorothiazide and chlorothiazide, consist of a benzothiadiazine backbone with an attached sulfonamide group. Thiazide-like diuretics, such as chlorthalidone and indapamide, lack the thiazide ring but demonstrate...
01:14Hepatic Drug Clearance: Role of Transporters
In the liver and bile canaliculi, influx and efflux transporters modification can influence intrinsic clearance. Transporters play a significant role in moving drugs within liver cells. Elaborate models, such as the Biopharmaceutical Classification System (BCS), are essential to relate transporters to drug disposition. This system categorizes drugs into four classes based on solubility and permeability, providing insights into elimination routes and the effects of transporters following oral...
01:16Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters
The pharmacogenetics of drug transporters is increasingly recognized as a critical factor influencing interindividual variability in drug absorption, distribution, and elimination. These membrane-bound proteins regulate drugs' movement across cellular barriers by actively pumping them out (efflux) or facilitating their uptake (influx). Among the major transporter families, ATP-binding cassette (ABC) and solute carrier (SLC) transporters play particularly prominent roles. Genetic polymorphisms...
01:31ABC Transporters: Exporter
ATP-binding cassette or ABC transporter is the largest superfamily of integral membrane proteins. The transporters have transmembrane-binding domains (TMDs) and nucleotide-binding domains (NBDs). The TMDs are specific to their substrates, whereas the NBDs are similar to engines that complete ATP hydrolysis to complete the substrate transport. They can be full transporters consisting of two TMDs and NBDs, half transporters with one TMD and NBD, while some encoded with a single TMD or NBD are...
01:27ABC Transporters: Importer
ATP-binding cassette or ABC transporters are a class of ATP-driven pumps that hydrolyze ATP to move solutes across the membrane. They can be grouped into importers and exporters. While exporters are present in all domains of life, importers exist only in bacteria and some plants.
In bacteria, based on the number of transmembrane helices and the chemical nature of their substrates, the ABC importers can be divided into three types:
In bacteria, based on the number of transmembrane helices and the chemical nature of their substrates, the ABC importers can be divided into three types:
01:16Methods for Studying Drug Absorption: In vitro
In vitro experiments are crucial for understanding the transport and absorption of drugs through biological materials. These studies employ varied methods such as the diffusion cell method, the everted sac technique, and the everted ring technique.
The diffusion cell method uses a two-compartment cell, including a donor compartment with the drug solution, which simulates the environment where the drug is applied, and a receptor compartment with a buffer solution, which simulates the environment...
The diffusion cell method uses a two-compartment cell, including a donor compartment with the drug solution, which simulates the environment where the drug is applied, and a receptor compartment with a buffer solution, which simulates the environment...