Effect of metoprolol and verapamil administered separately and concurrently after single doses on liver blood flow and drug disposition.
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.
Bauer
L A
LA
Department of Pharmacy, University of Washington, Seattle 98195-7630, USA.
Horn
J R
JR
Maxon
M S
MS
Easterling
T R
TR
Shen
D D
DD
Strandness
D E
DE
D000328:Adult; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D006339:Heart Rate / Q000187:drug effects; D006499:Hepatic Artery / Q000187:drug effects / Q000502:physiology; D006503:Hepatic Veins / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008099:Liver / Q000098:blood supply; D008102:Liver Circulation / Q000187:drug effects*; D008297:Male; D008790:Metoprolol / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011169:Portal Vein / Q000187:drug effects / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014700:Verapamil / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D014700:Verapamil; D008790:Metoprolol