Linked Life Data

21233217

Source:http://linkedlifedata.com/resource/pubmed/id/21233217

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2011-3-17
pubmed:abstractText
3-(1H-Indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (I-387) is a novel indole compound with antitubulin action and potent antitumor activity in various preclinical models. I-387 avoids drug resistance mediated by P-glycoprotein and showed less neurotoxicity than vinca alkaloids during in vivo studies. We examined the pharmacokinetics and metabolism of I-387 in mice as a component of our preclinical development of this compound and continued interest in structure-activity relationships for antitubulin agents. After a 1 mg/kg intravenous dose, noncompartmental pharmacokinetic analysis in plasma showed that clearance (CL), volume of distribution at steady state (Vd(ss)), and terminal half-life (t(1/2)) of I-387 were 27 ml per min/kg, 5.3 l/kg, and 7 h, respectively. In the in vitro metabolic stability study, half-lives of I-387 were between 10 and 54 min by mouse, rat, dog, monkey, and human liver microsomes in the presence of NADPH, demonstrating interspecies variability. I-387 was most stable in rat liver microsomes and degraded quickly in monkey liver microsomes. Liquid chromatography-tandem mass spectrometry was used to identify phase I metabolites. Hydroxylation, reduction of a ketone group, and O-demethylation were the major metabolites formed by the liver microsomes of the five species. The carbonyl group of I-387 was reduced and identified as the most labile site in human liver microsomes. The results of these drug metabolism and pharmacokinetic studies provide the foundation for future structural modification of this pharmacophore to improve stability of drugs with potent anticancer effects in cancer patients.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1521-009X
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
39
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
636-43
pubmed:meshHeading
pubmed-meshheading:21233217-Animals, pubmed-meshheading:21233217-Antimitotic Agents, pubmed-meshheading:21233217-Benzophenones, pubmed-meshheading:21233217-Biotransformation, pubmed-meshheading:21233217-Dogs, pubmed-meshheading:21233217-Drug Stability, pubmed-meshheading:21233217-Half-Life, pubmed-meshheading:21233217-Haplorhini, pubmed-meshheading:21233217-Humans, pubmed-meshheading:21233217-Hydroxylation, pubmed-meshheading:21233217-Indoles, pubmed-meshheading:21233217-Injections, Intravenous, pubmed-meshheading:21233217-Metabolic Detoxication, Phase I, pubmed-meshheading:21233217-Metabolic Detoxication, Phase II, pubmed-meshheading:21233217-Mice, pubmed-meshheading:21233217-Microsomes, Liver, pubmed-meshheading:21233217-NADP, pubmed-meshheading:21233217-P-Glycoprotein, pubmed-meshheading:21233217-Rats, pubmed-meshheading:21233217-Species Specificity, pubmed-meshheading:21233217-Structure-Activity Relationship
pubmed:year
2011
pubmed:articleTitle
Biotransformation of a novel antimitotic agent, I-387, by mouse, rat, dog, monkey, and human liver microsomes and in vivo pharmacokinetics in mice.
pubmed:affiliation
Division of Pharmaceutics, College of Pharmacy, Ohio State University, Columbus, Ohio, USA.
pubmed:publicationType
Journal Article