Effect of Metoprolol and Verapamil Administered Separately and Concurrently after Single Doses on Liver Blood Flow and Drug Disposition

• Published in: Journal of clinical pharmacology 2000-05, Vol.40 (5), p.533-543
• Main Authors: Bauer, Larry A., Horn, John R., Maxon, M. Scot, Easterling, Thomas R., Shen, Danny D., Strandness Jr, D. E.
• Format: Article
• Language: English
• Subjects: Adult; Antihypertensive agents; Antihypertensive Agents - pharmacokinetics; Antihypertensive Agents - pharmacology; Area Under Curve; Biological and medical sciences; Blood Pressure - drug effects; Calcium Channel Blockers - pharmacokinetics; Calcium Channel Blockers - pharmacology; Cardiac Output - drug effects; Cardiovascular system; 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; Medical sciences; Metoprolol - blood; Metoprolol - pharmacokinetics; Metoprolol - pharmacology; Pharmacology. Drug treatments; 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
• ISSN: 0091-2700; 1552-4604
• 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.