Adequate tumour quinidine levels for multidrug resistance modulation can be achieved in vivo

Area of Science:

• Pharmacology
• Oncology
• Biochemistry

Background:

• Multidrug resistance (MDR) is a significant challenge in cancer therapy.
• P-glycoprotein (P-gp) is a key mediator of the MDR phenotype.
• Concerns exist regarding inadequate tumor drug levels due to high plasma protein binding of MDR modulators.

Purpose of the Study:

• To investigate tumor penetration and effective levels of quinidine, a potential MDR modulator.
• To address concerns about high plasma protein binding limiting modulator efficacy in tumors.

Main Methods:

• Mice bearing human MDR-positive xenografts received intraperitoneal quinidine.
• Plasma and tumor quinidine levels were measured after 2 hours.
• Tumor biopsy samples from patients receiving oral quinidine were analyzed for drug levels.

Main Results:

• Mean plasma quinidine levels in mice were 1.9 µg/ml (5.1 µmol/l).
• Comparable plasma and tumor quinidine levels were observed in both mice and human patients.
• Achieved tumor levels were effective in vitro for MDR modulation.

Conclusions:

• Quinidine achieves adequate concentrations within tumors, comparable to plasma levels.
• High plasma protein binding does not appear to limit effective tumor drug levels for quinidine.
• These results encourage further clinical trials of quinidine and other MDR modulators in human cancers.