title: The pharmacokinetics and tissue distribution of the glucosylceramide synthase inhibitor miglustat in the rat.
abstract: Miglustat (Zavesca) is a reversible inhibitor of glucosylceramide synthase, which catalyses the first step in the glucosylceramide biosynthetic pathway, and is approved for therapy in patients with type 1 Gaucher disease. The present report describes the pharmacokinetic profile of miglustat in the rat with a focus on tissue distribution. Experiments were performed with radiolabeled miglustat itself and with a perbutyrated prodrug, the latter being readily converted to miglustat during gastrointestinal absorption and first pass metabolism. Miglustat was well absorbed and exhibited an oral bioavailability of 40-60%. Tissue distribution studies indicated the presence of miglustat in a number of organs and tissues that are considered of importance for the long-term therapeutic benefit, in particular the central nervous system, bone and lung. Miglustat was eliminated via renal clearance by a combination of glomerular filtration and active secretion. Hepatic clearance was negligible, as was the role of metabolism in the overall elimination process of miglustat in the rat.
authors.affiliation: Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland. alexander.treiber@actelion.com
authors.forename: A
authors.initials: A
authors.lastname: Treiber
authors.forename: O
authors.initials: O
authors.lastname: Morand
authors.forename: M
authors.initials: M
authors.lastname: Clozel
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002250:Carbon Radioisotopes / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D007275:Injections, Intravenous; D008297:Male; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D011355:Prodrugs; D014316:Tritium; D017485:1-Deoxynojirimycin; C059896:miglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase