VERAPAMIL STEREOISOMERISM - ENANTIOMERIC RATIOS IN PLASMA DEPENDENT ON PEAK CONCENTRATIONS, ORAL INPUT RATE, OR BOTH

Objective: To determine if R/S enantiomeric ratios of verapamil in plasma are affected by the changes in plasma concentration-time profiles of total verapamil, which result from administration of oral formulations with different input rates. Methods: Twelve young (19 to 37 years old) healthy men received 240 mg single oral doses of racemic verapamil as immediate-release (fasting) and sustained-release (fed) formulations in a randomized, crossover (7-day washout) study. Serial blood samples were taken over a 48-hour period, and PR intervals were measured at times close to blood drawings for the first 16 hours. Results: Marked enantiospecific disposition of verapamil occurred, with oral clearance values of 40.8, 25.3, and 121 ml/min/kg for the total verapamil, R-verapamil, and S-verapamil, respectively. Wide input-rate differences also occurred between the immediate- and sustained-release formulations (mean [% coefficient of variation]; peak concentration [C-max] [total], 327 [44%] versus 73 [58%] ng/ml; time to reach C-max [total], 1.71 [36%] versus 10.8 [62%] hours). The mean extent of total verapamil bioavailability from the sustained-release formulation was 73.3% of the immediate-release formulation. The R/S ratios at C-max (total) and at several other time periods were lower, with the immediate-release formulation for both verapamil (R/S = 4.52 [13%] versus 5.83 [18%]; p < 0.01) and norverapamil (R/S = 2.48 [16%] versus 3.04 [19%]; p < 0.01). Conclusions: Significantly different R/S ratios of verapamil occurred in the plasma with oral formulations that had substantially different rates of input. With the immediate-release formulation the total verapamil C-max was higher than that observed with the sustained-release formulation, and the percentage of the pharmacologically more active S-verapamil in the total was also higher (lower R/S ratio). These findings were attributed to the concentration- and/or input-rate-related saturable hepatic first-pass metabolism of the S-verapamil.