Enantioselective kinetics of verapamil and norverapamil in isolated perfused rat livers.

The kinetics of the individual enantiomers of verapamil (VER) and its metabolite, norverapamil (NOR), were studied in isolated perfused rat livers (IPRLs) after administration of racemic drug or the preformed metabolite. After constant infusion of 20 micrograms/min of racemic VER to single-pass IPRLs, the hepatic availabilities (F) of the enantiomers were low (S-VER, 0.069 +/- 0.030; R-VER: 0.046 +/- 0.025) and stereoselective (S:R ratio, 1.6 +/- 0.2). After administration of similar doses, the F values of the preformed NOR enantiomers (S-NOR: 0.24 +/- 0.04; R-NOR, 0.10 +/- 0.02) were higher than those of the VER enantiomers. However, the stereoselectivity in F of NOR (S:R ratio, 2.2 +/- 0.1), was in the same direction of that of VER. Further, the fractions of R enantiomers unbound to bovine serum albumin in the perfusate were higher than those of their antipodes for both VER (R:S ratio, 1.9 +/- 0.1) and NOR (R:S ratio, 2.6 +/- 0.2). Therefore, for unbound moieties, modest stereoselectivity in the metabolism of VER in favor of the S-isomer and no stereoselectivity in the metabolism of NOR were observed. Overall, our data suggest that the stereoselective protein binding is a primary determinant of stereoselectivity in the hepatic availability of VER and NOR in IPRLs.