Steady state verapamil tissue distribution in the dog: differing tissue accumulation

Area of Science:

• Pharmacology
• Cardiovascular Physiology
• Drug Distribution Studies

Background:

• Verapamil is a calcium channel blocker used to treat cardiovascular conditions.
• Understanding verapamil's tissue distribution is crucial for predicting its efficacy and potential side effects.
• Previous studies have not fully elucidated the differential organ accumulation of verapamil.

Purpose of the Study:

• To quantify plasma and tissue concentrations of verapamil in dogs following sustained intravenous infusion.
• To determine the specific pattern of verapamil accumulation in various organs, including cardiac and extracardiac tissues.
• To correlate verapamil tissue concentrations with observed physiological effects, such as changes in blood pressure and cardiac conduction.

Main Methods:

• Sustained intravenous infusions of verapamil were administered to 11 dogs.
• Plasma, heart, and extracardiac tissue concentrations of verapamil were measured.
• Mean arterial blood pressure and P-R intervals were monitored.
• The incidence of atrioventricular block was recorded.

Main Results:

• Verapamil demonstrated significant organ-specific accumulation, with highest concentrations in the lungs and lowest in fat and skeletal muscle.
• Cardiac tissue showed differential accumulation, with higher levels in ventricular myocardium compared to atrial myocardium.
• Verapamil administration led to a decrease in mean arterial blood pressure and a significant increase in the P-R interval, with 6 dogs developing second-degree atrioventricular block.

Conclusions:

• Verapamil exhibits highly variable and organ-specific affinity, influencing its distribution and potential therapeutic or toxic effects.
• Differential accumulation within cardiac chambers (ventricle vs. atrium) occurs, suggesting varied electrophysiological impacts.
• These findings highlight the importance of considering tissue-specific drug distribution in verapamil pharmacokinetics and pharmacodynamics.