Related Experiment Video

Updated: Aug 9, 2026

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
13:22

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Published on: October 23, 2019

Gefitinib modulates the function of multiple ATP-binding cassette transporters in vivo

Markos Leggas1, John C Panetta, Yanli Zhuang

  • 1Departments of Pharmaceutical Sciences, Hematology-Oncology, and Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. mark.leggas@uky.edu

Cancer Research
|May 3, 2006
PubMed

Insights

Gefitinib, an epidermal growth factor receptor inhibitor, enhances oral drug absorption by blocking breast cancer resistance protein (BCRP) and P-glycoprotein (MDR1) transporters. This combination therapy may improve drug bioavailability and overcome drug resistance.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Drug Discovery

Background:

  • 4-anilinoquinazoline (4-AQ) derivatives like gefitinib are epidermal growth factor receptor tyrosine kinase inhibitors.
  • These molecules can inhibit ATP-binding cassette (ABC) transporter-mediated drug efflux, increasing the bioavailability of coadministered drugs.
  • Previous studies suggested breast cancer resistance protein (BCRP; ABCG2) as the primary target, but in vivo effects on other transporters remained unclear.

Purpose of the Study:

  • To investigate the in vivo effects of gefitinib on drug transporters, specifically breast cancer resistance protein (BCRP; ABCG2) and P-glycoprotein (MDR1; ABCB1).
  • To determine if gefitinib's transporter inhibition occurs at clinically relevant concentrations.
  • To explore the therapeutic implications of combining gefitinib with BCRP and MDR1 substrate drugs.

Main Methods:

  • Utilized Abcg2(-/-) and Mdr1(a/b)(-/-) knockout mice pretreated with gefitinib to assess oral absorption and systemic clearance of topotecan.
  • Employed engineered human cell lines to evaluate gefitinib's inhibition of BCRP and MDR1 transporter substrates.
  • Determined the concentration-dependent inhibition of BCRP and MDR1 by gefitinib.

Main Results:

  • Gefitinib pretreatment increased oral absorption and decreased systemic clearance of topotecan in both wild-type and knockout mice, indicating inhibition of multiple transporters.
  • Gefitinib demonstrated in vitro inhibition of both BCRP and MDR1, restoring vincristine sensitivity in MDR1-expressing cells.
  • Significant inhibition of both BCRP and MDR1 was observed at clinically relevant concentrations (1-5 micromol/L), with BCRP being inhibited more potently.

Conclusions:

  • Gefitinib inhibits both BCRP and MDR1 transporters in vivo at therapeutic concentrations.
  • Combining gefitinib or other 4-AQ molecules with BCRP and MDR1 substrates holds potential for improving oral drug absorption and overcoming drug resistance.
  • These findings support the broader therapeutic application of 4-AQ derivatives to enhance drug delivery and efficacy.

More Related Videos

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds13:34

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds

Published on: April 6, 2016

Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions10:26

Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions

Published on: December 20, 2017

Related Concept Videos

Carrier-Mediated Transport01:06

Carrier-Mediated Transport

Carrier-mediated transport is a pivotal process in drug absorption, particularly for lipid-insoluble drugs, and encompasses facilitated diffusion and active transport. Facilitated diffusion allows drugs to move along their concentration gradient without energy expenditure, while active transport utilizes ATP to drive drug movement against this gradient.
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
Active Transport01:14

Active Transport

Active transport is a critical biological process that allows cells to move solutes against an electrochemical gradient. This process requires direct energy input and is characterized by its selectivity, saturability, and susceptibility to competitive inhibition.
Primary active transporters, like Na+, K+ and -ATPase, directly utilize ATP to move ions across the membrane. These transporters play significant roles in various physiological processes. For instance, Na+, K+ and -ATPase maintain...
Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters01:16

Pharmacogenetics 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...