Plasma Protein Binding as an Optimizable Parameter for Acidic Drugs.
Administration, Intravenous
Administration, Oral
Adolescent
Adult
Aged
Animals
Anti-Inflammatory Agents
/ chemistry
Blood Proteins
/ metabolism
Cells, Cultured
Dogs
Drug Evaluation, Preclinical
Female
Half-Life
Healthy Volunteers
Hepatocytes
Humans
Hydrogen-Ion Concentration
Inflammation
/ blood
Male
Metabolic Clearance Rate
Middle Aged
Plasma
/ metabolism
Primary Cell Culture
Protein Binding
Pyrimidines
/ chemistry
Rats
Receptors, Interleukin-8B
/ antagonists & inhibitors
Sulfonamides
/ chemistry
Young Adult
Journal
Drug metabolism and disposition: the biological fate of chemicals
ISSN: 1521-009X
Titre abrégé: Drug Metab Dispos
Pays: United States
ID NLM: 9421550
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
20
03
2019
accepted:
17
05
2019
pubmed:
23
5
2019
medline:
21
4
2020
entrez:
23
5
2019
Statut:
ppublish
Résumé
The low volume of distribution associated with acidic molecules means that clearance (CL) must also be very low to achieve an effective half-life commensurate with once or twice daily dosing. Plasma protein binding (PPB) should not usually be considered a parameter for optimization, but in the particular case of acidic molecules, raising the PPB above a certain level can result in distribution volume becoming a constant low value equal to the distribution volume of albumin while acting to reduce CL through restricting hepatic and renal access of unbound drug. Thus effective half-life can be increased. Here we detail the approaches and lessons learned at AstraZeneca during the optimization of acidic CXC chemokine receptor 2 (CXCR2) antagonists for the oral drug treatment of inflammatory diseases, resulting in discovery and clinical testing of
Identifiants
pubmed: 31113795
pii: dmd.119.087163
doi: 10.1124/dmd.119.087163
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Blood Proteins
0
CXCR2 protein, human
0
N-(2-(2,3-difluoro-6-benzylthio)-6-(3,4-dihydroxybutan-2-yloxy)pyrimidin-4-yl)azetidine-1-sulfonamide
0
Pyrimidines
0
Receptors, Interleukin-8B
0
Sulfonamides
0
Types de publication
Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
865-873Informations de copyright
Copyright © 2019 The Author(s).