Linked Life Data

12093357

Source:http://linkedlifedata.com/resource/pubmed/id/12093357

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2002-7-2
pubmed:abstractText
The unexpected occurrence of idiosyncratic drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use or failure to release/withdrawal. This leads to considerable uncertainty in drug development and has led to attempts to try to predict a drug's potential to cause such reactions. The biotransformation of relatively inert drugs to highly reactive metabolites, commonly referred to as "bioactivation", is now recognized to be an obligatory step in several kinds of drug-induced adverse reactions. Reactive metabolites can be formed by most, if not all, of the enzymes that are involved in drug metabolism. A major theme explored in this review includes the diversity of oxidative bioactivation reactions on nitrogen-containing xenobiotics including drugs. A variety of Phase I enzymes including P450, MAO, and peroxidases bioactivate nitrogen-containing xenobiotics via direct oxidations on the nitrogen atom leading to reactive intermediates or by oxidation at an alternate site in the molecule; for the metabolite to be reactive via the latter sequence nitrogen participation in required. Examples of direct oxidations on nitrogen include the N-oxidation of aromatic amines (e.g. procainamide), single electron N-oxidation of imides (e.g. phenytoin), or alpha-carbon oxidations of arylalkyl- or alkylamines (e.g. mianserin), to reactive nitroso, nitrogen free radical and iminium species, respectively. Examples of indirect bioactivation are highlighted with aromatic amines (e.g. diclofenac) that undergo p-hydroxylation resulting in the formation of p-aminophenols, two-electron oxidation of which results in the formation of reactive quinoneimines. Potential strategies that could be utilized in the screening of novel bioactivation pathways are also discussed.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1389-2002
pubmed:author
pubmed:issnType
Print
pubmed:volume
3
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
379-424
pubmed:dateRevised
2004-11-17
pubmed:meshHeading
pubmed:year
2002
pubmed:articleTitle
On the diversity of oxidative bioactivation reactions on nitrogen-containing xenobiotics.
pubmed:affiliation
Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, Groton, CT 06340, USA. amit_kalgutkar@groton.pfizer.com
pubmed:publicationType
Journal Article, Review