Verapamil stereoisomerism: enantiomeric ratios in plasma dependent on peak concentrations, oral input rate, or both

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.

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.

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 [Cmax] [total], 327 [44%] versus 73 [58%] ng/ml; time to reach Cmax [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 Cmax (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).

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 Cmax 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.