Previously, clinical studies comparing generic and reference formulations of sustained-release (SR) verapamil tablets revealed significant increases in the PR interval in subjects given the generic formulation in the presence of food. To determine the mechanisms underlying these differences in pharmacodynamics, the present analyses examined the pharmacokinetics of these formulations in the presence and absence of food. After single or multiple doses in fasting subjects, AUCs, Cmaxs, and tmaxs were similar, suggesting that these formulations were bioequivalent in the fasted state. However, the generic formulation exhibited a higher AUC(0-6) in fed subjects, suggesting that this formulation may be absorbed more rapidly than the reference formulation when given with food. Analysis of AUC(0-6) showed that 34% of the subjects receiving the generic formulation exhibited rapid absorption, compared with only 8% receiving the reference formulation. Significant increases in the PR interval were seen in nine fed subjects receiving the generic formulation compared with two receiving the reference formulation. Similarly, three fed subjects receiving the generic drug who were rapid absorbers exhibited first-degree heart block, whereas this conduction disturbance was seen in only one fed subject receiving the reference formulation. Thus, increased conduction disturbances seen in subjects given the generic formulation with a meal likely reflect more rapid absorption of this formulation in the presence of food, resulting in an increase in the ratio of more potent to less potent enantiomers of verapamil in the systemic circulation.