Document Detail

Cytochrome p450 enzymes mechanism based inhibitors: common sub-structures and reactivity.
MedLine Citation:
PMID:  16248836     Owner:  NLM     Status:  MEDLINE    
The inhibition of human cytochrome P450s (CYPs) is one of the most common mechanisms which can lead to drug-drug interactions. The inhibition of CYPs can be reversible (competitive or non-competitive) or irreversible. Irreversible inhibition usually derives from activation of a drug by CYPs into a reactive metabolite, which tightly binds to the enzyme active site, leading to a long lasting inactivation. This process is called "mechanism based inhibition" or "suicide inhibition". The irreversible inactivation usually implies the formation of a covalent bond between the metabolite and the enzyme, which can lead to hapten formation and can in some cases trigger an autoimmune-response. For these reasons it is of utmost importance to study the mechanism of the CYP inhibition of new potential drugs as early as possible during the drug discovery process. The literature on CYPs is vast and covers numerous aspects of their biology and biochemistry, however to our knowledge there is no general and systematic review focusing on mechanism-based inhibitors; we have reviewed the literature and compiled all the available data on chemical entities, which are known to be CYP suicide inhibitors. Each compound is reported together with its chemical structure, the CYP isoform and the parameters describing the inactivation. Literature references are reported together with their PMID (PubMed ID number) to allow a fast retrieval of the papers. This review offers a quick reference to help predict liabilities of new chemical entities without carrying out extensive in vitro work, and will hopefully help in designing safer drugs.
E Fontana; P M Dansette; S M Poli
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Current drug metabolism     Volume:  6     ISSN:  1389-2002     ISO Abbreviation:  Curr. Drug Metab.     Publication Date:  2005 Oct 
Date Detail:
Created Date:  2005-10-26     Completed Date:  2005-12-14     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  100960533     Medline TA:  Curr Drug Metab     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  413-54     Citation Subset:  IM    
F. Hoffmann-La Roche Ltd., Pharmaceutical Research, Discovery DMPK, Basel, Switzerland.
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MeSH Terms
Cytochrome P-450 Enzyme System / antagonists & inhibitors*,  chemistry
Drug Interactions
Enzyme Inhibitors / chemistry,  pharmacology*
Isoenzymes / antagonists & inhibitors,  chemistry
Structure-Activity Relationship
Terminology as Topic
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Isoenzymes; 9035-51-2/Cytochrome P-450 Enzyme System

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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