The metabolism of alicyclic amines to reactive iminium ion intermediates

Abstract

The evidence implicating the formation of iminium ions as reactive intermediates in the metabolism of alicyclic amines has been reviewed. The mechanism of formation of iminium ions and their conversion to alpha-carbonyl compounds or demethylated amines is discussed. The use of a simple cyanide trapping technique for iminium ions has been demonstrated to monitor a large number of alicyclic drugs for iminium ion formation. The possible role of iminium ions in the pharmacology and toxicology of alicyclic amines is considered.

Recent density functional theory model calculations of drug metabolism by cytochrome P450

“…Nicotine is mainly metabolized in liver by cytochrome P450 2A6 (CYP2A6) [117][118][119][120][121]. The principal nicotine-metabolizing pathway of nicotine is 5 -hydroxylation to 5 -hydroxynicotine [122,123] which is further oxidized to cotinine immediately [124][125][126], another metabolic pathway is N-demethylation to nornicotine and formaldehyde [127][128][129]. A detailed understanding of the mechanism of CYP2A6-catalyzed nicotine metabolism could provide a valuable mechanistic base for rational design of novel smoking cessation drugs.…”

“…With this free energy barrier difference, the calculations predict product abundance that 5 -hydroxynicotine is preponderant over the N-(hydroxymethyl)nornicotine by roughly a factor of 18:1. Since the subsequent processes of 5 -hydroxylation and Nmethylhydroxylation are quite faster [124][125][126][127][128][129] than the hydroxylation reaction itself, we might expect this 18:1 ratio to be conserved and continue onward to the cotitine and nornicotine products in nicotine metabolism. The predicted preference of 5 -hydroxylation over N-methylhydroxylation is in agreement with the experimental observation that cotinine is the primary metabolite of nicotine [121,[131][132][133][134].…”

A Novel P450-Catalyzed Transformation of the 2,2,6,6-Tetramethyl Piperidine Moiety to a 2,2-Dimethyl Pyrrolidine in Human Liver Microsomes: Characterization by High Resolution Quadrupole-Time-of-Flight Mass Spectrometry and 1H-NMR

“…This frequently results in poor pharmacokinetic properties for the new drug candidates. The N-substituted piperidines are also prone to metabolic activation via the formation of reactive iminium ions that may covalently modify proteins and other cellular nucleophiles and potentially result in toxicity (Sayre et al, 1991;Gorrod and Aislaitner, 1994;Castagnoli et al, 1997). Iminium ion formation also presumably involves oxidation at the piperidine ring ␣-carbons (Castagnoli et al, 1997).…”

Metabolism, Pharmacokinetics, and Excretion of the 5-Hydroxytryptamine1BReceptor Antagonist Elzasonan in Humans

“…This was determined by both extensive washing of adducted protein with organic solvent as well as extended dialysis of adducted protein (data not shown). It should be noted that although alicyclic iminium ion metabolites are commonly observed for cyclic tertiary amine drugs (Gorrod and Aislaitner, 1994) and have been proposed as potentially reactive electrophiles (Overton et al, 1985), there has been no direct evidence to link such metabolites with toxicity. For example, the metabolism-dependent covalent incorporation of mianserin, which forms an iminium ion, into liver microsomes does not appear to correlate with toxicity (Roberts et al, 1991).…”