Verapamil plasma protein binding was studied in four groups of 12 subjects each: (1) normal subjects; (2) patients with moderate renal insufficiency and patients requiring dialysis; (3) patients 1 to 4 days after coronary artery surgery; and (4) patients undergoing cardiac catheterization. In normal subjects, plasma protein binding of verapamil was 89.6 +/- 0.17% and was concentration independent over a range of 35 to 1,557 ng/ml, which includes the usual clinical plasma range. In normal subjects, plasma protein binding of verapamil was not affected by addition of its major metabolite, norverapamil, in ratios of 1.2 to 26.3 (norverapamil/verapamil) or by the addition of 10 micrograms of warfarin. The plasma protein binding of verapamil was not altered in the postsurgical state or in the dialysis patients. Verapamil protein binding was initially lower in the cardiac catheterization patients (mean = 86.34 +/- 2.13%, p less than 0.001) than in normal subjects and was still lower (mean = 83.29 +/- 3.04%, p less than 0.02) after heparinization. There was also a small increase in binding in the patients with renal insufficiency (p less than 0.05). Plasma protein binding of verapamil in mongrel dogs (mean = 90.7%) was the same order. We found verapamil to be approximately 90% bound in man and dogs and not markedly changed by any of the conditions studied.

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The effect of propafenone on the pharmacokinetics and pharmacologic effects of warfarin was studied in healthy normal male volunteer subjects. Each drug was administered alone for 1 week followed by a combined administration for 1 additional week. Blood samples were analyzed for propafenone and warfarin concentrations and the effect of each treatment on the prothrombin time was assessed. The concurrent administration of warfarin did not produce any changes in the absorption or disposition kinetics of propafenone. Concurrent propafenone administration did lead to a reduction in the clearance of warfarin, resulting in an average increase of 38% in the mean steady-state plasma warfarin concentration. During the combined therapy phase, the prothrombin time increased significantly (P less than 0.01) from the "warfarin alone" phase. We conclude from this study that the concomitant administration of propafenone and warfarin may lead to an enhanced anticoagulant effect that may require a reduction in the warfarin dose.