The Biotransformation of Nitrogen Containing Xenobiotics to Lactams

Authors: Vickers S.; Polsky S.L.

Source: Current Drug Metabolism, Volume 1, Number 4, December 2000 , pp. 357-389(33)

Publisher: Bentham Science Publishers

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Abstract:

The metabolism of nitrogen heterocyclics may lead to lactam formation. In early studies on xenobiotic metabolism lactams were identified as metabolites of nicotine, cyproheptadine, tremorine and prolintane. Now, because of the increasing availability of powerful analytical techniques, there are many instances of lactams being identified as metabolites. Lactam metabolites are formed from either iminium ions or carbinolamines. These two intermediates may have distinct mechanisms of formation but they can interconvert. There is evidence that the iminium ions are oxidized to lactams by aldehyde oxidases (cytosolic molybdenum hydroxylases). The tissue distribution and enzyme activities of aldehyde oxidase have been studied in several animal species. However, it is also known that iminium ions can undergo spontaneous hydrolysis to the corresponding carbinolamine. If the latter is stable it may undergo oxidation by cytochrome P-450 to form the lactam. Thus, species differences in lactam formation might be caused by differences in the concentrations of either cytochrome P450 isozymes or aldehyde oxidases. It appears that lactam formation is an end stage in the metabolism of N -heterocycles in that it is unlikely that the lactam will undergo hydrolysis to the corresponding amino acid. Such amino acids probably arise from the amino aldehydes that may be produced from ring opening of unstable carbinolamine intermediates. When microsomal preparations are incubated with the appropriate substrate in the presence of sodium cyanide the iminium ion may be trapped to produce a cyano compound. Such reactions have led to the proposal that iminium ions might react with nucleophilic sites of cellular macromolecules and so contribute to both the pharmacology and toxicology of N-heterocyclic compounds. Other pathways for the formation of lactam metabolites involve the internal cyclization of precursor metabolites, e.g. the self-condensation of an aldehyde group (formed during metabolism) with a neighboring amide group. However, spontaneous ring closures of amino acids to form lactams seem unlikely since it would be anticipated that the amino acid residue would exist as a stable zwitterion under physiological conditions. Thus, it is unlikely that lactams will undergo futile metabolism via hydrolytic ring opening followed by ring closure. Under extreme conditions such unanticipated ring closures may occur and the conditions of metabolite isolation may contribute to the occurrence of artifacts.

Keywords: Biotransformation; Nitrogen Containig Xenobiotics; Zaleplon; Irinotecan; piperidones; Pyrrolidinones; ketopiperazines; Morpholinones

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389200003338929

Publication date: 2000-12-01

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Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.

The Biotransformation of Nitrogen Containing Xenobiotics to Lactams

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