Interspecies differences in enantioselective mono-N-dealkylation of disopyramide by human and mouse liver microsomes
Echizen, H.; Mochizuki, K.; Tani, M.; Ishizaki, T.
Journal of Pharmacology and Experimental Therapeutics 268(3): 1518-1525
1994
ISSN/ISBN: 0022-3565 PMID: 8138963 Document Number: 430383
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, mu-M) was mediated by the high-affinity components. The mean (+-S.D.) affinity constant (K-m) of the high-affinity component for S-(+)-DP (4.86 +- 2.66 mu-M) was significantly (P lt .05) lower than that for R-(-)-DP (24.61 +- 17.52 mu-M), whereas no difference was observed between the maximum velocities (V.) for S-(+)- and R-(-)-DP. The mean intrinsic clearance (CL-int), defined as V-max/K-m, of the high-affinity component for S-(+)-DP was significantly greater (P lt .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 lt .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 V-max for the high-affinity component of mouse microsomes was about 6- to 8-fold greater than that of human's, the differences in K-m were at most 2.5-fold. In addition, metabolic competition between the enantiomers also occurred with mouse microsomes. Erythromycin inhibited the metabolism of both DP enantiomers, but the enantioselective inhibition behavior (e.g., IC-50) differed between the two species. These results suggest that 1) the microsomal metabolism of DP enantiomers appears to share a common enzyme component(s) in humans and mice, 2) an enantioselective difference in the affinity of a common microsomal enzyme(s) may explain that in in vivo hepatic clearance in humans and 3) the DP metabolism in humans is similar to that in mice regarding product enantioselectivity, enzyme affinity and susceptibility to a CYP3A-specific metabolic inhibition, but differs substantially regarding enzyme capacity.