Linked Life Data

11860340

Source:http://linkedlifedata.com/resource/pubmed/id/11860340

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2002-3-7
pubmed:abstractText
A pulsed ultrafiltration-mass spectrometric screening method has been developed to evaluate the metabolic stability of drugs. Pooled human liver microsomes containing cytochrome P450 enzymes were trapped by an ultrafiltration membrane in a stirred flow-through chamber, and eight beta-blocker drugs including acebutolol, alprenolol, atenolol, metoprolol, oxprenolol, pindolol, propranolol, and timolol were flow-injected through the chamber along with the cofactor NADPH. The ultrafiltrate was collected, concentrated and analyzed by using liquid chromatography-tandem mass spectrometry (LC-MS-MS) in order to quantitate the unmetabolized fraction of each drug. The metabolic stability of each beta-blocker was determined based on the difference between the corresponding LC-MS-MS peak areas of an experimental incubation and a control without NADPH. A flow-through incubation method, pulsed ultrafiltration metabolic screening minimizes the potential for product feed back inhibition of cytochrome P450 enzymes. The importance of this phenomenon was illustrated by the observation that the metabolic stability of the set of beta-blocker drugs measured using pulsed ultrafiltration more closely resembled the in vivo stability than that determined using a conventional batch incubation with microsomes or an incubation with human hepatocytes. Since a mixture of compounds was analyzed, the relative metabolic stability of each compound could be assessed by comparison to the other compounds in the incubation. This approach might be particularly useful for the ranking of a directed library of drug leads with respect to metabolic stability and then the selection of lead compounds for further drug development.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
1386-2073
pubmed:author
pubmed:issnType
Print
pubmed:volume
5
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
59-64
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2002
pubmed:articleTitle
Screening drugs for metabolic stability using pulsed ultrafiltration mass spectrometry.
pubmed:affiliation
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood St., Chicago, IL 60612-7231, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S.