QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.106.012286v1 34/12/2044    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gu, C. Articles by Voorman, R. L. Search for Related Content PubMed PubMed Citation Articles by Gu, C. Articles by Voorman, R. L.

Metabolic Aromatization of N-Alkyl-1,2,3,4-Tetrahydroquinoline Substructures to Quinolinium by Human Liver Microsomes and Horseradish Peroxidase

Pfizer Global Research and Development, Pharmacokinetics Dynamics & Metabolism (C.G., R.C., G.S.W., R.L.V.), and Department of Chemistry (D.D.H.), Ann Arbor, Michigan

Metabolic aromatization of xenobiotics is an unusual reaction with some documented examples. For instance, the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to the neurotoxic pyridinium ion metabolite 1-methyl-4-phenylpyridinium by monoamine oxidase (MAO) B in the brain has been of interest to a number of investigators. It has also been reported that although the aromatization of N-methyl-tetrahydroisoquinoline occurs with MAO B, the metabolism does not proceed for its isomer, N-methyl-tetrahydroquinoline, by the same enzyme. The aromatization of an N-alkyl-tetrahydroquinoline substructure was identified during in vitro metabolite profiling of compound A, which was designed as a potent renin inhibitor for the treatment of hypertension. The N-alkylquinolinium metabolite of compound A was identified by liquid chromatography-tandem mass spectrometry of human liver microsomal incubates and proton NMR of the isolated metabolite. Further in vitro metabolism studies with a commercially available chemical (compound B), containing the same substructure, also generated an N-alkylquinolinium metabolite. In vitro cytochrome P450 (P450) reaction phenotyping of compound A revealed that the metabolism was catalyzed exclusively by CYP3A4. Although compound B was a substrate for several P450 isoforms, its quinolinium metabolite was also generated predominantly by CYP3A4. Neither compound A nor compound B was a substrate of MAOs. The quinolinium metabolites were readily produced by horseradish peroxidase, suggesting that aromatization of the N-alkyltetrahydroquinoline could occur via a mechanism involving single electron transfer from nitrogen. Although dihydro intermediates from the tetrahydroquinoline substrates were not observed in the formation of quinolinium metabolites, cyanide trapping results indicated the occurrence of iminium intermediates.

This article has been cited by other articles:

				D. Dalvie, W. Chen, C. Zhang, A. D. Vaz, T. A. Smolarek, L. M. Cox, J. Lin, and R. S. Obach Pharmacokinetics, Metabolism, and Excretion of Torcetrapib, a Cholesteryl Ester Transfer Protein Inhibitor, in Humans Drug Metab. Dispos., November 1, 2008; 36(11): 2185 - 2198. [Abstract] [Full Text] [PDF]

				C. Prakash, W. Chen, M. Rossulek, K. Johnson, C. Zhang, T. O'Connell, M. Potchoiba, and D. Dalvie Metabolism, Pharmacokinetics, and Excretion of a Cholesteryl Ester Transfer Protein Inhibitor, Torcetrapib, in Rats, Monkeys, and Mice: Characterization of Unusual and Novel Metabolites by High-Resolution Liquid Chromatography-Tandem Mass Spectrometry and 1H Nuclear Magnetic Resonance Drug Metab. Dispos., October 1, 2008; 36(10): 2064 - 2079. [Abstract] [Full Text] [PDF]

				H. Sun, W. J. Ehlhardt, P. Kulanthaivel, D. L. Lanza, C. A. Reilly, and G. S. Yost Dehydrogenation of Indoline by Cytochrome P450 Enzymes: A Novel "Aromatase" Process J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 843 - 851. [Abstract] [Full Text] [PDF]