Quantitative mapping of metabolites of imipramine and desipramine in plasma samples by gas chromatographic-mass spectrometry.
Imipramine and desipramine are known to metabolize primarily by demethylation and hydroxylation. Hydroxy metabolites, 2-hydroxyimipramine and 2-hydroxydesipramine, are reported to be pharmacologically active by in vitro studies. We now report a simple gas chromatographic-mass spectrometric selected ion-monitoring (SIM) method for hydroxy metabolites of imipramine and desipramine from plasma samples using deuterated analogues as internal standards. d4-Internal standards for imipramine, desipramine, and their 2-hydroxy derivatives, were prepared in our laboratory and added to plasma samples, extracted at pH 9 with ethyl acetate, then at pH greater than 11 with hexane-isopropanol. The extracts were combined and evaporated under nitrogen. The trifluoroacetyl derivatives were prepared using N-methyl-bis-trifluoroacetamide and analyses were performed using GC-MS selected ion-monitoring in the electron ionization mode. Hydroxylation to 2-hydroxy metabolites varied widely between subjects. We also noticed in vivo methylation of desipramine to imipramine as a pathway of its metabolism in 15% of the subjects. It is suggested that plasma levels of all active metabolites must be considered in the assessment of the relationship of plasma levels of the drug to clinical response.
D001711:Biotransformation; D003891:Desipramine / Q000097:blood*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007099:Imipramine / Q000097:blood*
D007099:Imipramine; D003891:Desipramine