title: The metabolism and excretion of galantamine in rats, dogs, and humans.
abstract: Galantamine is a competitive acetylcholine esterase inhibitor with a beneficial therapeutic effect in patients with Alzheimer's disease. The metabolism and excretion of orally administered (3)H-labeled galantamine was investigated in rats and dogs at a dose of 2.5 mg base-Eq/kg body weight and in humans at a dose of 4 mg base-Eq. Both poor and extensive metabolizers of CYP2D6 were included in the human study. Urine, feces, and plasma samples were collected for up to 96 h (rats) or 168 h (dogs and humans) after dosing. The radioactivity of the samples and the concentrations of galantamine and its major metabolites were analyzed. In all species, galantamine and its metabolites were predominantly excreted in the urine (from 60% in male rats to 93% in humans). Excretion of radioactivity was rapid and nearly complete at 96 h after dosing in all species. Major metabolic pathways were glucuronidation, O-demethylation, N-demethylation, N-oxidation, and epimerization. All metabolic pathways observed in humans occurred in at least one animal species. In extensive metabolizers for CYP2D6, urinary metabolites resulting from O-demethylation represented 33.2% of the dose compared with 5.2% in poor metabolizers, which showed correspondingly higher urinary excretion of unchanged galantamine and its N-oxide. The glucuronide of O-desmethyl-galantamine represented up to 19% of the plasma radioactivity in extensive metabolizers but could not be detected in poor metabolizers. Nonvolatile radioactivity and unchanged galantamine plasma kinetics were similar for poor and extensive metabolizers. Genetic polymorphism in the expression of CYP2D6 is not expected to affect the pharmacodynamics of galantamine.
authors.affiliation: Department of Preclinical Pharmacokinetics, Johnson & Johnson Pharmaceutical Research and Development, a division of Janssen Pharmaceutica N.V., Beerse, Belgium. gmannens@prdbe.jnj.com
authors.forename: G S J
authors.initials: GS
authors.lastname: Mannens
authors.forename: C A W
authors.initials: CA
authors.lastname: Snel
authors.forename: J
authors.initials: J
authors.lastname: Hendrickx
authors.forename: T
authors.initials: T
authors.lastname: Verhaeghe
authors.forename: L
authors.initials: L
authors.lastname: Le Jeune
authors.forename: W
authors.initials: W
authors.lastname: Bode
authors.forename: L
authors.initials: L
authors.lastname: van Beijsterveldt
authors.forename: K
authors.initials: K
authors.lastname: Lavrijsen
authors.forename: J
authors.initials: J
authors.lastname: Leempoels
authors.forename: N
authors.initials: N
authors.lastname: Van Osselaer
authors.forename: A
authors.initials: A
authors.lastname: Van Peer
authors.forename: W
authors.initials: W
authors.lastname: Meuldermans
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000378:metabolism* / Q000652:urine; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D005702:Galantamine / Q000097:blood / Q000378:metabolism* / Q000652:urine; D006801:Humans; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002800:Cholinesterase Inhibitors; D005702:Galantamine