Anthelmintics Are Substrates and Activators of Nematode P Glycoprotein

Correlation between loss of efficacy of macrocyclic lactone heartworm anthelmintics and P-glycoprotein genotype.

Macrocyclic lactone (ML) molecules have been used for heartworm control for more than 25 years. However, in recent years, there have been reports of loss of efficacy of ML heartworm preventatives against Dirofilaria immitis in some locations in the United States. Macrocyclic lactone resistance is a common problem in nematode parasites of livestock, and more recently, evidence of ivermectin resi...

Rapid identification of P-glycoprotein substrates and inhibitors.

Identifying molecules that interact with P-glycoprotein (P-gp) is important for drug discovery but is also generally reliant on time-consuming in vitro and in vivo studies. As an alternative approach, the current study applied pharmacophore models and database screening to rapidly retrieve molecules that bind as substrates or inhibitors for P-gp from commercial databases and then confirmed thei...

C-Loperamide and its N-desmethyl radiometabolite are avid substrates for brain P-glycoprotein efflux

Synthetic hydrophobic peptides are substrates for P-glycoprotein and stimulate drug transport.

P-Glycoprotein functions as an ATP-driven active efflux pump for many natural products and chemotherapeutic drugs. Hydrophobic peptides have been shown to block drug uptake by P-glycoprotein, indicating that they might be transport substrates. The present study examines the interaction of the synthetic peptide series NAc-LnY-amide with the multidrug transporter. Several peptides in this series ...

Functional characterization of the rat mdr1b encoded P-glycoprotein: not all inducing agents are substrates.

The multidrug resistance (mdr) genes encode P-glycoproteins, integral membrane proteins which function as drug efflux transporters. Exposure of animals in vivo and cells in vitro to a variety of xenobiotics leads to increased mdr1 gene expression and higher levels of P-glycoprotein. This response may protect cells from the cytotoxic effects of these compounds. In this investigation we functiona...