Apparent stereoselectivity in propafenone uptake by human and rat erythrocytes

The distribution of propafenone (PPF) enantiomers between the plasma and red blood cells (RBCs) was investigated using human and rat blood. In separate experiments, effects of incubation time (15-60 min), blood concentration (100-5000 ng ml-1), and plasma proteins on the RBC uptake of the enantiomers were studied. In both humans and rats, the distribution of propafenone enantiomers into RBCs was rapid, extensive, and stereoselective. However, the extent of RBC uptake and the direction of stereoselectivity were different in these two species. In humans, preferential distribution of (-)-PPF into RBCs resulted in lower plasma concentrations for this enantiomer, whereas in rat plasma, (-)-PPF was the dominant enantiomer. When the plasma was replaced with buffer, the stereoselectivity in the RBC uptake of the enantiomers was abolished. This suggested that stereoselective protein binding may be responsible for this phenomenon. A direct measurement of the extent of binding of PPF enantiomers to rat and human plasma proteins further confirmed this. Moreover, the distribution of the enantiomers in RBCs was not affected by low temperatures or addition of ouabain, suggesting passive diffusion as the underlying mechanism. These results suggest that stereoselective red blood cell uptake may be responsible, at least in part, for the differences in the plasma pharmacokinetics of PPF enantiomers observed after the drug administration to humans and rats.