Ma. Robinson et R. Mehvar, ENANTIOSELECTIVE DISTRIBUTION OF VERAPAMIL AND NORVERAPAMIL INTO HUMAN AND RAT ERYTHROCYTES - THE ROLE OF PLASMA-PROTEIN BINDING, Biopharmaceutics & drug disposition, 17(7), 1996, pp. 577-587
In this in vitro study, the distribution of the enantiomers of verapam
il (VER) and its active metabolite, norverapamil (NOR), into the red b
lood cells (RBCs) of humans and rats was investigated using a chiral l
iquid chromatographic assay. When plasma was replaced with buffer, the
distribution of VER and NOR enantiomers into both human and rat RBCs
was substantial (RBC:blood concentration ratios, 1.39-1.79), non-stere
oselective, concentration (125-1000 ng mL(-1)) linear, and species ind
ependent. However, in the presence of plasma, the RBC distribution of
VER and NOR was stereoselective, with opposite stereoselectivity for h
uman (S > R) and rat (R > S) blood. Additionally, the presence of plas
ma caused a reduction in the extent of RBC distribution for both VER a
nd NOR enantiomers and in some cases resulted in nonlinearity in the R
BC distribution of the enantiomers. Plasma protein binding studies rev
ealed opposite stereoselectivity in the free fractions in human (S > R
) and rat (R > S) plasma for both VER and NOR. These data suggest that
the stereoselective protein binding is responsible for the apparent s
tereoselectivity in the RBC distribution of VER and NOR. The data are
also in agreement with the opposite stereoselectivity in the plasma co
ncentrations of VER observed in vivo in rats and humans.