Linked Life Data

12228184

Source:http://linkedlifedata.com/resource/pubmed/id/12228184

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2002-9-13
pubmed:abstractText
Liver microsomes, and more recently cryopreserved hepatocytes, are commonly used in the in vitro characterization of the metabolism of new xenobiotics. The flavin-containing monooxygenases (FMO) are a major non p450 oxidase present in liver microsomes and hepatocytes. Since FMO is known to be thermally labile, and this enzyme may be involved in the metabolic clearance of some drugs, we sought to more completely characterize the metabolic competency of this enzyme in cryopreserved hepatocytes and in liver microsomes preincubated under various conditions using benzydamine as an in vitro and in vivo probe. The metabolism of benzydamine to its major metabolite, the N-oxide, is mediated by FMO3 in humans. We found that the in vitro microsomal t(1/2) was 70% longer when incubations were prewarmed at 37 degrees C in the absence of NADPH compared with prewarming in the presence of an NADPH-regenerating system, and N-oxide formation was inhibited >99%. Interestingly, the in vivo clearance predicted from these incubations and from human hepatocytes overpredicted the observed clearance of benzydamine in humans (>10.5 versus 2.4 ml/min/kg). In contrast, rat hepatocytes successfully predicted rat in vivo benzydamine clearance to within approximately 30% (>68 versus 48 ml/min/kg). Benzydamine N-oxidation in liver microsomes from all common preclinical species demonstrated heat sensitivity. This information should be considered when extrapolating metabolism data of xenobiotics from these in vitro systems.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
30
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1087-93
pubmed:dateRevised
2005-11-17
pubmed:meshHeading
pubmed:year
2002
pubmed:articleTitle
Flavin-containing monooxygenase activity in hepatocytes and microsomes: in vitro characterization and in vivo scaling of benzydamine clearance.
pubmed:affiliation
Discovery Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Pfizer Inc, Eastern Point Rd, Groton, Connecticut 06340, USA. michael_fisher@groton.pfizer.com
pubmed:publicationType
Journal Article