Biotransformation of the disulfide of captopril in subcellular fractions of rat tissues
Lan, S.J.; Weinstein, S.H.; Migdalof, B.H.
Drug Metabolism and Disposition the Biological Fate of Chemicals 10(4): 306-311
1982
ISSN/ISBN: 0090-9556 PMID: 6126325 Document Number: 196651
The in vitro biotransformation of 14C-labeled captopril disulfide (CP-CP) was studied in the cytosol fraction of rat liver, kidney, lung and intestine, in the hemolysate of washed rat erythrocytes and in intact washed erythrocytes. Reduction of CP-CP to captopril (CP) was demonstrated in all these systems. Reduction of CP-CP to CP in the cytosol fraction of rat liver involved both enzymatic and nonenzymatic processes. The enzymatic processes required either NADPH or NADH as the cofactor and probably involved glutathione reductase, thiol-disulfide transhydrogenase and disulfide reductase. The nonenzymatic processes involved the thiol-disulfide interchange reactions between CP-CP and the sulfhydryl groups of endogenous low-MW sulfhydryl compounds and of proteins. Quantitative differences in the in vitro biotransformation of CP-CP were observed among preparations from the different organs. Initially CP was the major product in all tissue preparations. After 4 h, in the liver and lung preparations, CP-CP was biotransformed extensively and almost exclusively to CP; in the kidney and intestinal preparations the major metabolites were mixed disulfides of CP, presumably with glutathione and L-cysteine. CP-CP was extensively reduced to CP after incubation with the hemolysate of erythrocytes. Only a fraction (14%) of CP-CP was reduced to CP after 2 h of incubation with washed intact erythrocytes in the presence of D-glucose and no CP was formed in the absence of D-glucose. The low percentage of reduction of CP-CP by intact erythrocytes was attributed to limited permeability of the cell membrane to this compound. The small percentage of transport of CP-CP across the membrane may have been due to an active transport system.