Lack of interaction between verapamil and cimetidine

Nine healthy normal subjects received verapamil, 10 mg iv, before (control) and during cimetidine dosing (300 mg every 6 hours), and verapamil, 120 mg po, twice in the same manner. After intravenous doses, the t 1 2 (X ± SE: control, 3.60 ± 0.40 hours; cimetidine trial, 4.30 ± 0.60 hours), volume of distribution (5.8 ± 0.6 vs. 6.6 ± 0.9 L/kg), and total clearance (19.2 ± 1.5 vs. 18.4 ± 1.6 ml/min/kg) did not change during cimetidine dosing. After oral doses, the t 1 2 (4.25 ± 0.57 vs. 4.60 ± 0.70 hours), plasma AUC (585 ± 113 vs. 506 ± 82 ng/ml · hr) and absolute bioavailability (35% ± 7% vs. 30% ± 5%) did not differ between control and cimetidine trials, respectively. Five of the subjects also received lidocaine, 25 mg iv, once in the control state and once during the cimetidine regimen described above. Lidocaine clearance fell (665 ± 216 vs. 527 ± 134 ml/min; P < 0.05) during cimetidine therapy, resulting in a trend toward a longer t 1 2 (1.81 ± 0.41 vs. 2.44 ± 0.42 hours; 0.1 > P > 0.05) with no change in volume of distribution (1.77 ± 0.66 vs. 1.99 ± 0.81 L/kg). Verapamil pharmacodynamics (ECG PR interval, blood pressure, and heart rate) were evaluated after intravenous doses. A decrease in mean arterial pressure (8 ± 1 vs. 9 ± 2 mm Hg) and a reflex increase in heart rate (14 ± 3 vs. 17 ± 2 bpm) were no different in the control and cimetidine trials. After intravenous doses under a sigmoid E_max pharmacodynamic model, verapamil concentration at 50% maximal prolongation of PR interval from baseline did not differ between trials (27.5 ± 2.8 [control] vs. 24.3 ± 2.1 ng/ml), nor did the maximal PR prolongation differ (94 ± 36 [control] vs. 85 ± 20 msec). After oral verapamil doses under a linear pharmacodynamic model, the slope of the line describing the verapamil concentration vs. PR interval relationship (1.10 ± 0.61 [control] vs. 1.15 ± 0.56 msec/ng · mg^-1) and the defined y-intercept (-37 ± 21 [control] vs. -28 ± 15 msec) were no different between trials. Our data indicate that neither a pharmacokinetic nor a pharmacodynamic interaction between verapamil and cimetidine occur in vivo in man when therapeutic doses are administered, and that verapamil hepatic extraction after oral dosing is not affected by cimetidine, unlike extraction processes described for other high-clearance drugs.