Effect of metoprolol and verapamil administered separately and concurrently after single doses on liver blood flow and drug disposition

J Clin Pharmacol. 2000 May;40(5):533-43. doi: 10.1177/00912700022009152.


Nine healthy males participated in a double-blind, placebo-controlled, randomized, crossover study to determine the effects of verapamil and metoprolol administered alone and concurrently on blood flow through the hepatic artery and portal and hepatic veins and to detect a possible drug interaction between the two agents. Single oral doses of placebo/placebo, metoprolol (50 mg)/placebo, verapamil (80 mg)/placebo, or verapamil/metoprolol were separated by at least 14 days. Liver blood flow through individual hepatic vessels was measured up to 8 hours after dosage administration using a duplex Doppler ultrasound technique. Cardiac output, heart rate, blood pressure, stroke volume, and total peripheral resistance were measured for 3 hours after drug doses were given. In 5 subjects, pharmacokinetic parameters for total drug as well as S- and R-enantiomers were also measured. Verapamil given alone caused a rapid and intense increase in liver blood flow (hepatic artery = 50%, portal vein = 42%, hepatic vein = 55%) 0.75 to 1 hour after administration because of a decrease in total peripheral resistance and an increase in heart rate, stroke volume, and cardiac output. Metoprolol given alone caused a slow but prolonged decrease in liver blood flow (maximum decrease: hepatic artery = -54%, portal vein = -21%, hepatic vein = -27%) 4 hours after administration because of a decrease in heart rate and cardiac output. When the two agents were given together, a composite of the changes noted after separate administration was noted: a brief peak increase in liver blood flow at 0.33 to 1 hour followed by a slow, prolonged decrease that reached its maximum decline 4 to 5 hours postdose. During the combined phase, metoprolol and its enantiomers had an increased AUC and Cmax, while verapamil and its enantiomers had an increased AUC and t1/2. These pharmacokinetic changes were consistent with the magnitude and time course of liver blood flow changes through the hepatic artery and portal or hepatic veins.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Antihypertensive Agents / pharmacokinetics
  • Antihypertensive Agents / pharmacology*
  • Area Under Curve
  • Blood Pressure / drug effects
  • Calcium Channel Blockers / pharmacokinetics
  • Calcium Channel Blockers / pharmacology*
  • Cardiac Output / drug effects
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Interactions
  • Heart Rate / drug effects
  • Hepatic Artery / drug effects
  • Hepatic Artery / physiology
  • Hepatic Veins / drug effects
  • Hepatic Veins / physiology
  • Humans
  • Liver / blood supply
  • Liver Circulation / drug effects*
  • Male
  • Metoprolol / blood
  • Metoprolol / pharmacokinetics
  • Metoprolol / pharmacology*
  • Portal Vein / drug effects
  • Portal Vein / physiology
  • Regional Blood Flow / drug effects
  • Stroke Volume / drug effects
  • Time Factors
  • Vascular Resistance / drug effects
  • Verapamil / blood
  • Verapamil / pharmacokinetics
  • Verapamil / pharmacology*


  • Antihypertensive Agents
  • Calcium Channel Blockers
  • Verapamil
  • Metoprolol