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 the isolated perfused rat liver and after subcellular fractionation. The mannosidase inhibitor 1-deoxymannojirimycin (dMM) and the glucosidase inhibitor N-methyl-1-deoxynojirimycin (MedNM) exhibited minimal binding to albumin and reached liver concentrations that approximately equaled 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)degradation 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 fraction. We conclude that dMM and MedNM will likely inhibit liver enzymes when sufficiently high plasma levels are reached.
Faber
E D
ED
Department of Pharmacology and Therapeutics, University Centre for Pharmacy, University of Groningen, The Netherlands.
Proost
J H
JH
Oosting
R
R
Meijer
D K
DK
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D005959:Glucosidases / Q000037:antagonists & inhibitors*; D065089:Glycoside Hydrolase Inhibitors; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008361:Mannosidases / Q000037:antagonists & inhibitors; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D013347:Subcellular Fractions / Q000378:metabolism*; D000520:alpha-Glucosidases
D000998:Antiviral Agents; D065089:Glycoside Hydrolase Inhibitors; D017485:1-Deoxynojirimycin; D000135:Acid Phosphatase; D005959:Glucosidases; D008361:Mannosidases; C042059:glucosidase I; C046090:mannosyl-oligosaccharide 1,2-alpha-mannosidase; D000520:alpha-Glucosidases; C033424:N-methyldeoxynojirimycin