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 m etabolite. After constant infusion of 20 mu g/min of racemic VER to si ngle-pass IPRLs, the hepatic availabilities (F) of the enantiomers wer e low (S-VER, 0.069 +/- 0.030; R-VER: 0.046 +/- 0.025) and stereoselec tive (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. Ho wever, 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 ena ntiomers 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) an d NOR (R:S ratio, 2.6 +/- 0.2). Therefore, for unbound moieties, modes t stereoselectivity in the metabolism of VER in favor of the S-isomer and no stereoselectivity in the metabolism of NOR were observed. Overa ll, our data suggest that the stereoselective protein binding is a pri mary determinant of stereoselectivity in the hepatic availability of V ER and NOR in IPRLs.