Identification of the urinary metabolites of tacrine in the rat

RS Hsu, GM Shutske, EM Dileo, SM Chesson, AR Linville and RC Allen

Chemical Research Department, Hoechst-Roussel Pharmaceuticals.

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.

Volume 18, Issue 5, pp. 779-783, 09/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics

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