Interspecies differences in enantioselective mono-N-dealkylation of disopyramide by human and mouse liver microsomes

The interspecies differences in the enantioselective metabolism of disopyramide (DP) were studied with human and mouse liver microsomes. Mono-N-dealkylation of both DP enantiomers was biphasic, suggesting an involvement of two enzymes in the metabolism in both species. The human data indicated that the metabolism of both DP enantiomers at the therapeutic concentrations (i.e., 5-14 microM) was mediated by the high-affinity components. The mean (+/- S.D.) affinity constant (Km) of the high-affinity component for S-(+)-DP (4.86 +/- 2.66 microM) was significantly (P < .05) lower than that for R-(-)-DP (24.61 +/- 17.52 microM), whereas no difference was observed between the maximum velocities (Vmax) for S-(+)- and R-(-)-DP. The mean intrinsic clearance (CL(int)), defined as Vmax/Km, of the high-affinity component for S-(+)-DP was significantly greater (P < .01) than that for R-(-)-DP, consistent with the reported in vivo pharmacokinetic data. In contrast, the CL(int) of the low-affinity component for R-(-)-DP was significantly (P < .01) greater than that for S-(+)-DP. Coincubation of DP enantiomers as a racemate showed mutual competitive inhibition. With mouse liver microsomes, a preferential metabolism of S-(+)-DP over R-(-)-DP was also observed only for the high-affinity components. Although the mean Vmax for the high-affinity component of mouse microsomes was about 6- to 8-fold greater than that of human's, the differences in Km were at most 2.5-fold. In addition, metabolic competition between the enantiomers also occurred with mouse microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)