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What are inhibitors of ABCG2 pumps?

What are inhibitors of ABCG2 pumps?

As an efflux pump exhibiting a broad substrate specificity localized on cellular plasma membrane, ABCG2 excretes a variety of endogenous and exogenous substrates including chemotherapeutic agents, such as mitoxantrone and several tyrosine kinase inhibitors.

What is ABCG2 transporter?

ABCG2 is a constitutively expressed ATP-binding cassette (ABC) transporter that protects many tissues against xenobiotic molecules. Its activity affects the pharmacokinetics of commonly used drugs and limits the delivery of therapeutics into tumour cells, thus contributing to multidrug resistance.

What does ABCG2 do?

Normal Function The ABCG2 gene belongs to a group of genes called the ATP-binding cassette family; genes in this family provide instructions for making proteins that transport molecules across cell membranes. In the intestines, the ABCG2 protein helps release (secrete) a substance called urate into the urine.

What is ABCG2 pumps?

ATP-binding cassette (ABC), sub-family G, isoform 2 protein (ABCG2, also known as breast cancer resistance protein, BCRP) is a drug efflux pump and an important member of the ABC transporter superfamily. ABCG2 was identified independently by three separate groups in 1998 and 1999 [3–5].

What drugs are Pgp inhibitors?

Some common pharmacological inhibitors of P-glycoprotein include: amiodarone, clarithromycin, ciclosporin, colchicine, diltiazem, erythromycin, felodipine, ketoconazole, lansoprazole, omeprazole and other proton-pump inhibitors, nifedipine, paroxetine, reserpine, saquinavir, sertraline, quinidine, tamoxifen, verapamil.

What is ko143?

Ko 143 is a potent and selective breast cancer resistance protein multidrug transporter (BCRP) inhibitor (EC90 = 26 nM). Displays > 200-fold selectivity over P-gp and MRP-1 transporters. Increases intracellular drug accumulation and reverses BCRP-mediated multidrug resistance.

What do ABC transporters do?

ATP-binding cassette (ABC) transporters constitute a ubiquitous superfamily of integral membrane proteins that are responsible for the ATP-powered translocation of many substrates across membranes. The highly conserved ABC domains of ABC transporters provide the nucleotide-dependent engine that drives transport.

What is a BCRP inhibitor?

ABCG2, more commonly referred to as BCRP (Breast Cancer Resistance Protein), is an efflux transporter that serves two major drug transport functions. Firstly, it restricts the distribution of its substrates into organs such as the brain, testes, placenta, and across the gastrointestinal tract (GIT).

Is atorvastatin a P-gp inhibitor?

Although atorvastatin has been described as an inhibitor of P-gp, higher concentrations are required for maximal P-gp inhibition. Some of the best evidence of P-gp induction has been demonstrated between digoxin and rifampin. Rifampin, a well-known CYP450 inducer, was administered to patients also receiving digoxin.

What happens if P-gp is inhibited?

It reduces the oral availability of drugs that are its substrates. Like the enzymes involved in drug metabolism, substrates of P-glycoprotein can potentially act as inhibitors or inducers of its function. Inhibition of P-glycoprotein can result in increased bioavailability of the susceptible drug.

How many types of ABC transporters are there?

There are 48 ABC transporters in humans that can be subdivided by phylogenetic analysis into seven distinct subfamilies A-G [8,9].

What are the three components of the ABC transporter system?

1996), and the genes for the three components frequently form an operon (Higgins 1992). Importers and exporters represent the ABC transporters. ABC transporters include nucleotide binding domains (NBD1 and NBD2), transmembrane spanning domains (MSD1 and MSD2) and solute binding proteins (SBP1 and SBP2).

Which is the first inhibitor of ABCG2 in humans?

The first ABCG2 inhibitor reported was FTC, a mycotoxin produced by Aspergillus fumigatus (Rabindran et al., 1998, 2000). The in vivo use of FTC was unfortunately precluded due to its neurotoxicity.

How is ABCG2 overexpression related to cancer treatment?

ABCG2 overexpression can render the cancer cells resistant to the ABCG2 substrate chemotherapy agents, such as mitoxantrone, doxorubicin, SN-38, and several TKIs. To the best of our knowledge, no published clinical trial has ever succeeded in reversing the ABCG2-mediated MDR.

Which is an exogenous substrate of ABCG2 efflux pump?

As an efflux pump exhibiting a broad substrate specificity localized on cellular plasma membrane, ABCG2 excretes a variety of endogenous and exogenous substrates including chemotherapeutic agents, such as mitoxantrone and several tyrosine kinase inhibitors.

Where is ABCG2 found in the human body?

Moreover, in the normal tissues, ABCG2 is expressed on the apical membranes and plays a pivotal role in tissue protection against various xenobiotics. For this reason, ABCG2 is recognized to be an important determinant of the pharmacokinetic characteristics of its substrate drugs.