Rifampin Induces Expression of P-glycoprotein on the THP1 Cell-Derived Macrophages, Causing Decrease Intramacrophage...

Area of Science:

• Pharmacology
• Molecular Biology
• Infectious Diseases

Background:

• Rifampin (RIF) is a cornerstone in tuberculosis (TB) treatment.
• Drug-resistant TB poses a significant global health challenge due to diminished drug effectiveness.
• P-glycoprotein (P-gp) is a key efflux transporter involved in drug resistance.

Purpose of the Study:

• To investigate the impact of RIF on MDR1 gene (P-gp) expression in THP1 macrophages.
• To determine how RIF affects the intracellular concentration of the anti-TB drug prothionamide.
• To explore the role of P-gp in RIF's interaction with anti-TB medications.

Main Methods:

• THP1 macrophages were treated with RIF to assess MDR1 mRNA and protein levels.
• The effect of P-gp inhibitors (resveratrol, ketoconazole, cyclosporine A) on RIF-induced P-gp expression and drug accumulation was evaluated.
• Intracellular concentrations of rhodamine-123 and prothionamide were measured in RIF-treated macrophages.

Main Results:

• RIF significantly induced MDR1 protein and mRNA expression in stimulated THP1 macrophages.
• RIF treatment led to reduced intracellular concentrations of rhodamine-123 and prothionamide, indicating P-gp mediated efflux.
• P-gp inhibitors (resveratrol, ketoconazole) suppressed RIF-induced P-gp expression, while cyclosporine A increased intracellular drug levels.

Conclusions:

• RIF induces P-gp expression in macrophages, potentially decreasing the intracellular concentration of co-administered P-gp substrate drugs.
• Concurrent use of RIF with P-gp substrate drugs may compromise TB treatment efficacy due to reduced intracellular drug levels.
• Further research is needed to elucidate the clinical implications of RIF-induced P-gp modulation on TB treatment outcomes.