Physiological disposition of verapamil in man

Area of Science:

• Pharmacology
• Drug Metabolism
• Clinical Pharmacokinetics

Background:

• Verapamil is a widely used calcium channel blocker.
• Understanding its pharmacokinetic profile is crucial for effective therapeutic use.

Purpose of the Study:

• To determine the pharmacokinetic parameters of verapamil after intravenous and oral administration.
• To assess the extent of first-pass metabolism and oral bioavailability of verapamil.

Main Methods:

• Administration of 14C-D,L-verapamil intravenously (10 mg) and orally (80 mg) to five healthy volunteers.
• Quantification of plasma verapamil concentrations using mass fragmentography.
• Analysis of radioactivity in plasma, urine, and feces to assess absorption, distribution, metabolism, and excretion.

Main Results:

• Plasma verapamil concentrations declined bi-exponentially with distinct alpha and beta half-lives.
• Oral absorption was nearly complete, but bioavailability was low (10-22%) due to extensive first-pass metabolism.
• Significant biotransformation occurred, with minimal unchanged verapamil detected in plasma after both administration routes.

Conclusions:

• Verapamil undergoes substantial first-pass metabolism in humans, significantly limiting its oral bioavailability.
• The pharmacokinetic profile indicates rapid and extensive biotransformation, impacting its therapeutic efficacy and dosing.