Linked Life Data

15640381

Source:http://linkedlifedata.com/resource/pubmed/id/15640381

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2005-3-22
pubmed:abstractText
This study was carried out to determine the metabolic pathways of buspirone and cytochrome P450 (P450) isoform(s) responsible for buspirone metabolism in human liver microsomes (HLMs). Buspirone mainly underwent N-dealkylation to 1-pyrimidinylpiperazine (1-PP), N-oxidation on the piperazine ring to buspirone N-oxide (Bu N-oxide), and hydroxylation to 3'-hydroxybuspirone (3'-OH-Bu), 5-hydroxybuspirone (5-OH-Bu), and 6'-hydroxybuspirone (6'-OH-Bu) in HLMs. The apparent K(m) values for buspirone metabolite formation in pooled HLMs were 8.7 (1-PP), 34.0 (Bu N-oxide), 4.3 (3'-OH-Bu), 11.4/514 (5-OH-Bu), and 8.8 microM (6'-OH-Bu). CYP3A inhibitor ketoconazole (1 microM) completely inhibited the formation of all major metabolites in HLMs (0-16% of control), whereas the chemical inhibitor selective to other P450 isoforms had little or no inhibitory effect. Recombinant CYP3A4, CYP3A5, and CYP2D6 exhibited buspirone oxidation activities among nine P450 isoforms tested. The overall metabolism rate of 5 microM buspirone by CYP3A4 was 18-fold greater than that by CYP2D6 and 35-fold greater than that by CYP3A5. In a panel of HLMs from 16 donors, buspirone metabolism correlated well CYP3A activity (r2 = 0.85-0.96, rho < 0.0005), but not the activities of other P450 isoforms. The metabolism rates of buspirone in CYP2D6 poor-metabolizer genotype HLMs were comparable to those in pooled HLMs. Taken together, these data suggest that CYP3A, mostly likely CYP3A4, is primarily responsible for the metabolism of buspirone in HLMs.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
33
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
500-7
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Cytochrome P450 3A-mediated metabolism of buspirone in human liver microsomes.
pubmed:affiliation
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. mingshe.zhu@bms.com
pubmed:publicationType
Journal Article, In Vitro