Linked Life Data

12695341

Source:http://linkedlifedata.com/resource/pubmed/id/12695341

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2003-4-15
pubmed:abstractText
Voriconazole is a triazole antifungal agent with potent activity against a broad spectrum of clinically significant pathogens. In vivo and in vitro studies have demonstrated that voriconazole is extensively metabolized, with the major circulating metabolite resulting from N-oxidation. In the present study, we report on the human cytochrome P450 enzymes responsible for the generation of this metabolite. In human liver microsomes voriconazole N-oxidation exhibited biphasic kinetics with K(m1) of 8.1 microM, and K(m2) of 835 microM. Studies at 2500 microM voriconazole identified CYP3A4 as the low-affinity component, with activity correlating strongly with CYP3A4 activity in a bank of human liver microsomes (r = 0.90) and inhibited by ketoconazole. At 25 microM, voriconazole N-oxidation showed strong correlation with CYP2C19 and CYP3A4 activity (r = 0.77 and 0.74, respectively) and was inhibited by both sulfaphenazole and ketoconazole. Incubations with recombinant enzymes suggested both CYP2C9 and CYP2C19 as high-affinity enzymes (K(m) values of 20 and 3.5 microM, respectively). Further studies used chemical inhibitors in human liver microsomes prepared from individual donors, including two CYP2C19 poor metabolizers. No inhibition was observed with sulfaphenazole, indicating a minor role for CYP2C9 in human liver, but inhibition by ketoconazole was most potent in the CYP2C19 poor metabolizer livers, suggesting an increased role for CYP3A4 in individuals lacking CYP2C19. These data indicate that voriconazole is a substrate for CYP2C9, CYP2C19, and CYP3A4, with CYP2C9 involvement being minimal in human liver microsomes. Genotype status for CYP2C19 and/or coadministration of drugs that modulate CYP2C19 or CYP3A4 activities could effect voriconazole plasma levels.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Antifungal Agents, http://linkedlifedata.com/resource/pubmed/chemical/Cyclic N-Oxides, http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 Enzyme System, http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Ketoconazole, http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines, http://linkedlifedata.com/resource/pubmed/chemical/Quinidine, http://linkedlifedata.com/resource/pubmed/chemical/Sulfaphenazole, http://linkedlifedata.com/resource/pubmed/chemical/Theophylline, http://linkedlifedata.com/resource/pubmed/chemical/Triazoles, http://linkedlifedata.com/resource/pubmed/chemical/furafylline, http://linkedlifedata.com/resource/pubmed/chemical/voriconazole
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
31
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
540-7
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2003
pubmed:articleTitle
Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole.
pubmed:affiliation
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Sandwich, Kent, United Kingdom. ruth_hyland@sandwich.pfizer.com
pubmed:publicationType
Journal Article, In Vitro