The abamectin derivative ivermectin is a potent P-glycoprotein inhibitor

Area of Science:

• Biochemistry
• Pharmacology
• Molecular Biology

Background:

• P-glycoprotein (Pgp) mediates multidrug resistance (MDR) in cancer cells.
• SDZ PSC 833, a cyclosporin D derivative, is a potent Pgp inhibitor.
• SDZ PSC 833 treatment in vivo affects tolerability to other compounds, suggesting Pgp substrate interactions.

Purpose of the Study:

• To investigate whether ivermectin, a pesticide, also inhibits Pgp function.
• To compare the Pgp inhibitory activity of ivermectin with known inhibitors like SDZ PSC 833.
• To determine if ivermectin acts as a Pgp substrate and/or inhibitor.

Main Methods:

• In vivo studies assessing tolerability changes after SDZ PSC 833 administration.
• In vitro short-term assays measuring Pgp function inhibition.
• Assays quantified the restoration of Pgp probe retention in MDR cells to parental cell levels.

Main Results:

• Ivermectin, similar to cyclosporin A (CsA), caused central nervous system dysfunction in mice treated with SDZ PSC 833, implying Pgp neutralization at the blood-brain barrier.
• Ivermectin demonstrated significant Pgp function inhibition in both murine (MDR-P388) and human (MDR-CEM) leukemia cell lines.
• Ivermectin's inhibitory activity was comparable to SDZ PSC 833 in MDR-CEM cells and only slightly weaker in MDR-P388 cells.

Conclusions:

• Ivermectin exhibits Pgp inhibitory properties, potentially reversing multidrug resistance.
• Ivermectin functions as both a substrate and an inhibitor of P-glycoprotein, similar to CsA and FK-506.
• These findings highlight ivermectin's potential role in modulating drug transport and efficacy.