Linked Life Data

17132764

Source:http://linkedlifedata.com/resource/pubmed/id/17132764

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2007-1-24
pubmed:abstractText
Human liver microsomes have typically resulted in marked underprediction of in vivo human intrinsic clearance (CL(int)); therefore, the utility of cryopreserved hepatocytes as an alternative in vitro system has become an important issue. In this study, 10 compounds (tolbutamide, diclofenac, S-warfarin, S-mephenytoin, dextromethorphan, bufuralol, quinidine, nifedipine, testosterone, and terfenadine) were selected as substrate probes for CYP2C9, 2C19, 2D6, and 3A4, and the kinetics of metabolite formation (n = 14 pathways) were investigated in three individual lots of cryopreserved hepatocytes and in a pool of human liver microsomes. For the majority of the compounds, lower unbound K(M) or S(50) values were observed in hepatocytes compared with microsomes, on average by 50% over a 200-fold range (0.5-140 microM). Expressed on an equivalent liver weight basis, a good correlation between microsomal and hepatocyte V(max) values was observed for most pathways greater than 5 orders of magnitude (0.16-216 nmol/min/g liver). Unbound hepatocyte CL(int) (CL(int,u)) values, when scaled to the whole liver (range 0.38-4000 ml/min/kg), were on average 2.5-fold higher than microsomal CL(int,u) values, with the exception of tolbutamide and diclofenac, for which lower hepatocellular CL(int,u) values were observed. Hepatocyte predicted CL(int) values were compared with human in vivo CL(int) values, and to supplement our data, in vitro data from cryopreserved hepatocytes were collated from four other published sources. These data show that for 37 drugs, there is, on average, a 4.5-fold under-prediction of the in vivo CL(int) using cryopreserved hepatocytes, representing a significant reduction in prediction bias compared with human microsomes.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
35
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
293-301
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Evaluation of cryopreserved human hepatocytes as an alternative in vitro system to microsomes for the prediction of metabolic clearance.
pubmed:affiliation
Centre for Applied Pharmacokinetic Research, School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't