Linked Life Data

18538760

Source:http://linkedlifedata.com/resource/pubmed/id/18538760

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1-3
pubmed:dateCreated
2008-7-28
pubmed:abstractText
The aim of the present research was to characterize the pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel quinazolinone-based dipeptidyl peptidase-4 (DPP-4) inhibitor. Alogliptin potently inhibited human DPP-4 in vitro (mean IC(50), ~ 6.9 nM) and exhibited > 10,000-fold selectivity for DPP-4 over the closely related serine proteases DPP-2, DPP-8, DPP-9, fibroblast activation protein/seprase, prolyl endopeptidase, and tryptase (IC(50) > 100,000 nM). Absolute oral bioavailability of alogliptin in rats, dogs, and monkeys was 45%, 86%, and 72% to 88%, respectively. After a single oral dose of alogliptin, plasma DPP-4 inhibition was observed within 15 min and maximum inhibition was > 90% in rats, dogs, and monkeys; inhibition was sustained for 12 h in rats (43%) and dogs (65%) and 24 h in monkeys (> 80%). From E(max) modeling, 50% inhibition of DPP-4 activity was observed at a mean alogliptin plasma concentration (EC(50)) of 3.4 to 5.6 ng/ml (10.0 to 16.5 nM) in rats, dogs, and monkeys. In Zucker fa/fa rats, a single dose of alogliptin (0.3, 1, 3, and 10 mg/kg) inhibited plasma DPP-4 (91% to 100% at 2 h and 20% to 66% at 24 h), increased plasma GLP-1 (2- to 3-fold increase in AUC(0-20 min)) and increased early-phase insulin secretion (1.5- to 2.6-fold increase in AUC(0-20 min)) and reduced blood glucose excursion (31%-67% decrease in AUC(0-90 min)) after oral glucose challenge. Alogliptin (30 and 100 mg/kg) had no effect on fasting plasma glucose in normoglycemic rats. In summary, these data suggest that alogliptin is a potent and highly selective DPP-4 inhibitor with demonstrated efficacy in Zucker fa/fa rats and potential for once-daily dosing in humans.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0014-2999
pubmed:author
pubmed:issnType
Print
pubmed:day
28
pubmed:volume
589
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
306-14
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed-meshheading:18538760-Administration, Oral, pubmed-meshheading:18538760-Animals, pubmed-meshheading:18538760-Biological Availability, pubmed-meshheading:18538760-Blood Glucose, pubmed-meshheading:18538760-Dipeptidyl Peptidase 4, pubmed-meshheading:18538760-Dipeptidyl-Peptidase IV Inhibitors, pubmed-meshheading:18538760-Disease Models, Animal, pubmed-meshheading:18538760-Dogs, pubmed-meshheading:18538760-Dose-Response Relationship, Drug, pubmed-meshheading:18538760-Drug Administration Schedule, pubmed-meshheading:18538760-Glucagon-Like Peptide 1, pubmed-meshheading:18538760-Glucose Metabolism Disorders, pubmed-meshheading:18538760-Humans, pubmed-meshheading:18538760-Hypoglycemic Agents, pubmed-meshheading:18538760-Insulin, pubmed-meshheading:18538760-Insulin Resistance, pubmed-meshheading:18538760-Macaca fascicularis, pubmed-meshheading:18538760-Male, pubmed-meshheading:18538760-Piperidines, pubmed-meshheading:18538760-Rats, pubmed-meshheading:18538760-Rats, Sprague-Dawley, pubmed-meshheading:18538760-Rats, Zucker, pubmed-meshheading:18538760-Uracil
pubmed:year
2008
pubmed:articleTitle
Pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel inhibitor of dipeptidyl peptidase-4, in rats, dogs, and monkeys.
pubmed:affiliation
Takeda San Diego Inc, San Diego, CA 92121, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't