title: Identification of the urinary metabolites of tacrine in the rat.
abstract: Tacrine (THA) is a potent cholinesterase inhibitor being studied for the treatment of Alzheimer's disease. The metabolism and excretion of THA were studied in rats following a single oral dose of 20 mg/kg of THA. The results show THA was extensively metabolized in rats after oral administration. Three major urinary metabolites were isolated by HPLC on a semi-prep analytical phenyl column, and subsequent purification of the individual fractions on a semi-prep analytical cyano column. The major metabolic pathways involve the hydroxylation of the saturated ring at positions 1, 2, and 4. The structures of the metabolites 9-amino-1,2,3,4-tetrahydroacridin-1-ol (1-OH-THA), 9-amino-1,2,3,4-tetrahydroacridin-2-ol (2-OH-THA), and 9-amino-1,2,3,4-tetrahydroacridin-4-ol (4-OH-THA) were determined by electron impact mass spectrometry and/or 1H-NMR, and compared with synthetic references. The urinary excretion of THA and metabolites was quantitated by HPLC with UV detection. About 60% of the oral dose was eliminated as total THA, 1-OH-THA, 2-OH-THA, and 4-OH-THA over a 48-hr collection interval; and the non-conjugated THA and hydroxylated metabolites accounted for 45% of the dose.
authors.affiliation: Chemical Research Department, Hoechst-Roussel Pharmaceuticals.
authors.forename: R S
authors.initials: RS
authors.lastname: Hsu
authors.forename: G M
authors.initials: GM
authors.lastname: Shutske
authors.forename: E M
authors.initials: EM
authors.lastname: Dileo
authors.forename: S M
authors.initials: SM
authors.lastname: Chesson
authors.forename: A R
authors.initials: AR
authors.lastname: Linville
authors.forename: R C
authors.initials: RC
authors.lastname: Allen
mesh_terms: D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D011919:Rats, Inbred Strains; D012015:Reference Standards; D013056:Spectrophotometry, Ultraviolet; D013619:Tacrine / Q000737:chemistry / Q000378:metabolism / Q000652:urine*
chemical_list: D013619:Tacrine