Dataset Information

Demin2013 - PKPD behaviour - 5-Lipoxygenase inhibitors

ABSTRACT: Demin2013 - PKPD behaviour - 5-Lipoxygenase inhibitors This model is described in the article: Systems pharmacology models can be used to understand complex pharmacokinetic-pharmacodynamic behavior: an example using 5-lipoxygenase inhibitors. Demin O, Karelina T, Svetlichniy D, Metelkin E, Speshilov G, Demin O Jr, Fairman D, van der Graaf PH, Agoram BM. CPT Pharmacometrics Syst Pharmacol 2013; 2: e74 Abstract: Zileuton, a 5-lipoxygenase (5LO) inhibitor, displays complex pharmaokinetic (PK)-pharmacodynamic (PD) behavior. Available clinical data indicate a lack of dose-bronchodilatory response during initial treatment, with a dose response developing after ~1-2 weeks. We developed a quantitative systems pharmacology (QSP) model to understand the mechanism behind this phenomenon. The model described the release, maturation, and trafficking of eosinophils into the airways, leukotriene synthesis by the 5LO enzyme, leukotriene signaling and bronchodilation, and the PK of zileuton. The model provided a plausible explanation for the two-phase bronchodilatory effect of zileuton-the short-term bronchodilation was due to leukotriene inhibition and the long-term bronchodilation was due to inflammatory cell infiltration blockade. The model also indicated that the theoretical maximum bronchodilation of both 5LO inhibition and leukotriene receptor blockade is likely similar. QSP modeling provided interesting insights into the effects of leukotriene modulation.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e74; doi:10.1038/psp.2013.49; advance online publication 11 September 2013. This model is hosted on BioModels Database and identified by: BIOMD0000000490. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

DISEASE(S): Asthma

SUBMITTER: Vijayalakshmi Chelliah

PROVIDER: BIOMD0000000490 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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			Action	DRS
	BIOMD0000000490?filename=BIOMD0000000490-biopax2.owl	Owl
	BIOMD0000000490?filename=BIOMD0000000490-biopax3.owl	Owl
	BIOMD0000000490?filename=BIOMD0000000490.m	Other
	BIOMD0000000490?filename=BIOMD0000000490.pdf	Pdf
	BIOMD0000000490?filename=BIOMD0000000490.png	Other

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Systems pharmacology models can be used to understand complex pharmacokinetic-pharmacodynamic behavior: an example using 5-lipoxygenase inhibitors.

Demin O O Karelina T T Svetlichniy D D Metelkin E E Speshilov G G Demin O O Fairman D D van der Graaf P H PH Agoram B M BM

CPT: pharmacometrics & systems pharmacology 20130911

Zileuton, a 5-lipoxygenase (5LO) inhibitor, displays complex pharmaokinetic (PK)-pharmacodynamic (PD) behavior. Available clinical data indicate a lack of dose-bronchodilatory response during initial treatment, with a dose response developing after ~1-2 weeks. We developed a quantitative systems pharmacology (QSP) model to understand the mechanism behind this phenomenon. The model described the release, maturation, and trafficking of eosinophils into the airways, leukotriene synthesis by the 5LO ...[more]

PMID: 24026253

Publication: 1/4

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