Identification of a 3-hydroxylated tacrine metabolite in rat and man: metabolic profiling implications and pharmacology.
Discrepancies in urinary metabolic profiles in rats administered tacrine (1) suggested the presence of an unidentified metabolite of 1. Chromatographic methods were developed that allowed isolation of a metabolite fraction containing both 1-hydroxytacrine (2) and an unknown metabolite from rat urine. Mass spectral analysis indicated this metabolite to be a monohydroxylated derivative, which upon two dimensional COSY NMR analysis could be assigned as 3-hydroxytacrine (4). This structural assignment was confirmed by independent synthesis of 4. Compound 4 was also identified as a human urinary metabolite of 1. Biologically, 4 was found to have in vitro human red blood cell acetylcholinesterase inhibitory activity similar to that of 2 and 4-hydroxytacrine (5) and approximately 8-fold less than that of 1. These results underscore the need to conduct rigorous structural identification studies, especially in cases where isomeric metabolites are possible, in assessing the accuracy of chromatographic profiling techniques.
Pool
W F
WF
Department of Pharmacology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Woolf
T F
TF
Reily
M D
MD
Caprathe
B W
BW
Emmerling
M R
MR
Jaen
J C
JC
D000110:Acetylcholinesterase / Q000097:blood; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000652:urine*; D002851:Chromatography, High Pressure Liquid; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D015394:Molecular Structure; D051381:Rats; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000652:urine*
C100737:3-hydroxytacrine; D002800:Cholinesterase Inhibitors; D013619:Tacrine; D000110:Acetylcholinesterase