DISPOSITION OF GLYCOSIDASE INHIBITORS IN THE ISOLATED-PERFUSED RAT-LIVER - HEPATOBILIARY AND SUBCELLULAR CONCENTRATION GRADIENTS OF 1-DEOXYMANNOJIRIMYCIN AND N-METHYL-1-DEOXYNOJIRIMYCIN

The hepatic disposition of two glycosidase inhibitors was studied in t he isolated perfused rat liver and after subcellular fractionation. Th e mannosidase inhibitor 1-deoxymannojirimycin (dMM) and the glucosidas e inhibitor N-methyl-1-deoxynojirimycin (MedNM) exhibited minimal bind ing to albumin and reached liver concentrations that approximately equ aled their medium concentrations, after 30 min (MedNM) or 90 min (dMM) . Within 2 hr 0.5% of the dose of MedNM and 2.9% of dMM were excreted in bile. No metabolites were found for MedNM, whereas minor (bio)degra dation was inferred for dMM. After subcellular fractionation, dMM and MedNM were found predominantly in the cytosolic fraction. Compared to the other particulate fractions, MedNM was elevated in the microsomal fraction. and both compounds were slightly enriched in the lysosomal f raction. We conclude that dMM and MedNM will likely inhibit liver enzy mes when sufficiently high plasma levels are reached.