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

Nine healthy males participated in a double-blind, placebo-controlled, rand omized, crossover study to determine the effects of verapamil and metoprolo l administered alone and concurrently on blood pow through the hepatic arte ry and portal and hepatic veins and to detect a possible drug interaction b etween the two agents. Single oral doses of placebo/ placebo, metoprolol (5 0 mg)/placebo, verapamil (80 mg)/ placebo, or verapamil/metoprolol were sep arated by at least 14 days. Liver blood pow through individual hepatic vess els was measured up to 8 hours after dosage administration using a duplex D oppler ultrasound technique. Cardiac output, heart rate, blood pressure, st roke volume and total peripheral resistance were measured for 3 hours after drug doses were given. In 5 subjects, pharmacokinetic parameters for fetal drug as well as S- and R-enantiomers were also measured. Verapamil given a lone caused a rapid and intense increase in liver blood pow (hepatic artery = 50%, portal vein = 42%, hepatic vein = 55%) 0.75 to I hour after adminis tration because of a de-crease in total peripheral resistance and an increa se 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 a fter 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 blo od flow at 0.33 to 1 hour followed by a slow, prolonged decrease that reach ed ifs maximum decline 4 50 5 hours postdose. During the combined phase, me toprolol and its enantiomers had an increased AUC and C-max, while verapami l and its enantiomers had an increased AUC and t(1/2). These pharmacokineti c changes were consistent with the magnitude and time course of liver blood flow changes through the hepatic artery and portal or hepatic veins. (C) 2 000 the American College of Clinical Pharmacology.