Linked Life Data

19216580

Source:http://linkedlifedata.com/resource/pubmed/id/19216580

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2009-2-16
pubmed:abstractText
Guidance from the Food and Drug Administration on drug interaction studies does not include a specific section on contributions of metabolites to observed inhibitory drug-drug interactions, and the quantitative role of drug metabolites in inhibitory drug-drug interactions is not presently known. The current work was undertaken to evaluate what fraction of inhibitors of common drug-metabolizing enzymes [cytochrome P450 (P450) 1A2, 2E1, 2D6, 2C9, 2C19, 2C8, 2B6, and 3A4] have circulating metabolites that may contribute to observed in vivo interactions. A literature analysis was conducted using the Metabolism and Transport Drug Interaction Database to identify all precipitants (i.e., inhibitors) that cause more than a 20% increase in the area under the plasma concentration-time curve (AUC) of marker substrates. The database, PubMed, and product labels were then used to determine whether circulating metabolites were present after administration of these inhibitors. Of the total of 129 inhibitors identified, 106 were confirmed to have metabolites that circulate in plasma. An additional 14 inhibitors were identified that are extensively metabolized but whose metabolites either have not been identified or have not been investigated. Hence, only 7% of the inhibitors did not have circulating metabolites. Of the 21 potent inhibitors (>or=5-fold increase in AUC) currently known, 17 had circulating metabolites, and the remaining four were all extensively metabolized. On the basis of available in vitro data, 24 of all of the inhibitors were mechanism-based inactivators of P450 enzymes, while 105 were characterized as reversible inhibitors. In vitro evaluation of inhibition potential was conducted for only 32% of the circulating metabolites of the inhibitors. In conclusion, circulating metabolites are often present with inhibitors of P450 enzymes, suggesting a need for increased efforts to characterize the inhibitory potency of metabolites of candidate drugs and for newer models for in vitro to in vivo extrapolations.
pubmed:grant
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1520-5010
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
22
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
294-8
pubmed:dateRevised
2011-9-26
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Qualitative analysis of the role of metabolites in inhibitory drug-drug interactions: literature evaluation based on the metabolism and transport drug interaction database.
pubmed:affiliation
Department of Pharmaceutics, University of Washington, P.O. Box 357610, Seattle, Washington 98195, USA. ni2@u.washington.edu
pubmed:publicationType
Journal Article, Review, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural