Linked Life Data

16415114

Source:http://linkedlifedata.com/resource/pubmed/id/16415114

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2006-3-22
pubmed:abstractText
A metabolic interaction between stiripentol (STP), an anticonvulsant agent that inhibits the activity of several cytochromes P450 (P450s), and clobazam (CLB), a 1,5-benzodiazepine, used in association with STP in severe myoclonic epilepsy in infancy was observed in vivo. This interaction was characterized in vitro using cDNA-expressed CYP3A4 and CYP2C19 (main P450 involved in CLB metabolism) to calculate K(i) and IC(50) of stiripentol in comparison with ketoconazole (CYP3A4 inhibitor) and omeprazole (CYP2C19 inhibitor). STP inhibited N-demethylation of CLB to N-desmethylclobazam (NCLB) mediated by CYP3A4 (noncompetitively) and CYP2C19 (competitively) with K(i) = 1.59 +/- 0.07 and 0.516 +/- 0.065 microM and IC(50) = 1.58 microM [95% confidence interval (CI95%) = 1.20-2.08] and 3.29 microM (CI95% = 1.87-5.79), respectively. STP inhibited also more strongly the 4'-hydroxylation of NCLB to 4'-hydroxy-N-desmethylclobazam by CYP2C19 [competitive interaction with K(i) = 0.139 +/- 0.025 microM and IC(50) = 0.276 microM (CI95% = 0.206-0.371)]. The inhibitory effect of STP on CLB demethylation by CYP3A4 was much weaker than that of ketoconazole [IC(50) = 0.023 microM (CI95% = 0.016-0.033)], whereas its effect on NCLB hydroxylation by CYP2C19 was much higher than that of omeprazole [IC(50) = 2.99 microM (CI95% = 2.11-4.24)]. The major in vitro inhibitory effect of STP on CLB metabolism and mostly on NCLB biotransformation is consistent with the changes in vivo in CLB and NCLB plasma concentrations in children treated by the association CLB/STP.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Anticonvulsants, http://linkedlifedata.com/resource/pubmed/chemical/Aryl Hydrocarbon Hydroxylases, http://linkedlifedata.com/resource/pubmed/chemical/Benzodiazepines, http://linkedlifedata.com/resource/pubmed/chemical/CYP2C19 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/CYP3A4 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 CYP3A, http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 Enzyme System, http://linkedlifedata.com/resource/pubmed/chemical/Dioxolanes, http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Ketoconazole, http://linkedlifedata.com/resource/pubmed/chemical/Mixed Function Oxygenases, http://linkedlifedata.com/resource/pubmed/chemical/Omeprazole, http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins, http://linkedlifedata.com/resource/pubmed/chemical/clobazam, http://linkedlifedata.com/resource/pubmed/chemical/stiripentol
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
34
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
608-11
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
In vitro and in vivo inhibitory effect of stiripentol on clobazam metabolism.
pubmed:affiliation
Department of Pharmacology, Université Paris-Descartes, Faculté de Médecine, Groupe Hospitalier Cochin St. Vincent de Paul, Paris, France.
pubmed:publicationType
Journal Article, Comparative Study, In Vitro, Research Support, Non-U.S. Gov't