STUDIES OF HUMAN URINARY AND BILIARY METABOLITES OF NORTRIPTYLINE WITH STABLE ISOTOPE LABELING

¹ Division of Clinical Pharmacology, University of Cincinnati College of Medicine, Cincinnati, Ohio; Lilly Research Laboratories, Indianapolis, Indiana

The readily recognized isotopic doublet in the mass spectra of chlorine-containing compounds (due to the natural abundance of the ³⁵Cl and ³⁷Cl isotopes) has proven to be useful in the study of the metabolism of chlorine containing drugs such as chiorpromazine. Since relatively few drugs contain elements having an appreciable natural abundance of more than one isotope, we have artificially created isotopic doublets to serve as conspicuous mass-spectral markers by mixing stable isotope labeled and unlabeled drugs. An equimolar mixture of unlabeled nortriptyline and trideuterium-labeled nortriptyline was administered to adult volunteers. When trifluoroacetylated basic urinary extracts were examined by gas chromatography-mass spectrometry, the parent drug and any metabolites retaining the labeled site were readily identified by the presence of the M, M+3 doublet. Mixtures containing dideuterium/nitrogen-15 labeled drug also were used in the studies of urinary metabolites and in studies of biliary metabolites. Metabolites present in insufficient quantities for mass spectral scanning were identified by mass fragmentography. In addition to unchanged nortriptyline, desmethylnortriptyline, lO-hydroxynortriptyline and 10-hydroxydesmethylnortriptyline were identified in urine by virtue of their near-equal intensity artificially created isotopic doublet. The same four compounds also were observed in human bile in proportions similar to those seen in urine.