Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2006-10-30
pubmed:abstractText
Aplidine is a potent marine anti-cancer drug and is currently being investigated in phase II clinical trials. However, the enzymes involved in the biotransformation of aplidine and thus its pharmacokinetics are not known yet. To assess the biotransformation pathways of aplidine and their potential implications for human pharmacology and toxicology, the in vitro metabolism of aplidine was characterized using incubations with human plasma, liver preparations, cytochrome P450 (CYP) and uridine diphosphoglucuronosyl transferase (UGT) supersomes in combination with HPLC analysis and cytotoxicity assays with cell lines. Aplidine was metabolised by carboxyl esterases in human plasma. Using CYP supersomes and liver microsomes, it was shown that aplidine was metabolised mainly by CYP3A4 and also by CYP2A6, 2E1 and 4A11. Four metabolites were observed after incubation with human liver microsomes, one formed by CYP2A6 (C-demethylation) and three by CYP3A4 (hydroxylation and/or C-dealkylation). No conjugation was observed in human liver S9 fraction. However, the aplidine metabolites formed by CYP were further conjugated by the phase II enzymes UGT, GST and SULT. In accordance with the findings in microsomes and CYP supersomes, a significant effect of specific CYP2A6, 2E1, 3A4 and 4A11 inhibitors on the cytotoxicity of aplidine in Hep G2 and IGROV-1 cells could be observed. These results provide evidence that CYP3A4 has a major role in metabolising aplidine in vitro with additional involvement of CYP2A6, 2E1, and 4A11. Further, the metabolites formed by CYPs can be conjugated by UGT, SULT and GST. These findings could help interpret the in vivo pharmacokinetics of aplidine.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, http://linkedlifedata.com/resource/pubmed/chemical/Aryl Hydrocarbon Hydroxylases, 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/Depsipeptides, http://linkedlifedata.com/resource/pubmed/chemical/Glucuronosyltransferase, http://linkedlifedata.com/resource/pubmed/chemical/Mixed Function Oxygenases, http://linkedlifedata.com/resource/pubmed/chemical/Nitrophenols, http://linkedlifedata.com/resource/pubmed/chemical/Phenylmethylsulfonyl Fluoride, http://linkedlifedata.com/resource/pubmed/chemical/aplidine, http://linkedlifedata.com/resource/pubmed/chemical/bis(4-nitrophenyl)phosphate, http://linkedlifedata.com/resource/pubmed/chemical/coumarin 7-hydroxylase
pubmed:status
MEDLINE
pubmed:month
Feb
pubmed:issn
0167-6997
pubmed:author
pubmed:issnType
Print
pubmed:volume
25
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
9-19
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:16633717-Antineoplastic Agents, pubmed-meshheading:16633717-Aryl Hydrocarbon Hydroxylases, pubmed-meshheading:16633717-Cell Line, Tumor, pubmed-meshheading:16633717-Cell Survival, pubmed-meshheading:16633717-Chromatography, High Pressure Liquid, pubmed-meshheading:16633717-Cytochrome P-450 CYP3A, pubmed-meshheading:16633717-Cytochrome P-450 Enzyme System, pubmed-meshheading:16633717-Cytosol, pubmed-meshheading:16633717-Depsipeptides, pubmed-meshheading:16633717-Female, pubmed-meshheading:16633717-Glucuronosyltransferase, pubmed-meshheading:16633717-Half-Life, pubmed-meshheading:16633717-Humans, pubmed-meshheading:16633717-Liver, pubmed-meshheading:16633717-Male, pubmed-meshheading:16633717-Metabolic Detoxication, Phase II, pubmed-meshheading:16633717-Microsomes, Liver, pubmed-meshheading:16633717-Mixed Function Oxygenases, pubmed-meshheading:16633717-Molecular Structure, pubmed-meshheading:16633717-Nitrophenols, pubmed-meshheading:16633717-Phenylmethylsulfonyl Fluoride, pubmed-meshheading:16633717-Spectrophotometry, Ultraviolet, pubmed-meshheading:16633717-Subcellular Fractions
pubmed:year
2007
pubmed:articleTitle
In vitro characterization of the human biotransformation pathways of aplidine, a novel marine anti-cancer drug.
pubmed:affiliation
Department of Pharmaceutical Sciences, Section of Biomedical Analysis, Division of Drug Toxicology, Utrecht University, Utrecht, The Netherlands.
pubmed:publicationType
Journal Article