Faber E D, Proost J H, Oosting R, Meijer D K
Department of Pharmacology and Therapeutics, University Centre for Pharmacy, University of Groningen, The Netherlands.
Pharm Res. 1994 Jan;11(1):144-50. doi: 10.1023/a:1018970400323.
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.
在离体灌注大鼠肝脏和亚细胞分级分离后，研究了两种糖苷酶抑制剂的肝脏处置情况。甘露糖苷酶抑制剂1-脱氧甘露基野尻霉素（dMM）和葡萄糖苷酶抑制剂N-甲基-1-脱氧野尻霉素（MedNM）与白蛋白的结合极少，在30分钟（MedNM）或90分钟（dMM）后，肝脏浓度大致等于其培养基浓度。在2小时内，MedNM剂量的0.5%和dMM剂量的2.9%经胆汁排泄。未发现MedNM有代谢产物，而推断dMM有轻微（生物）降解。亚细胞分级分离后，dMM和MedNM主要存在于胞质部分。与其他颗粒部分相比，MedNM在微粒体部分升高，且两种化合物在溶酶体部分略有富集。我们得出结论，当达到足够高的血浆水平时，dMM和MedNM可能会抑制肝脏酶。
