An in vitro toolbox to accelerate anti-malarial drug discovery and development.
Anti-malarial drugs
Biorelevant solubility
Blood to plasma partitioning
CYP inhibition
Ionization constant
Microsomal stability
Partition coefficient
Physiologically-based pharmacokinetic modelling
Protein binding
Journal
Malaria journal
ISSN: 1475-2875
Titre abrégé: Malar J
Pays: England
ID NLM: 101139802
Informations de publication
Date de publication:
02 Jan 2020
02 Jan 2020
Historique:
received:
11
08
2019
accepted:
14
12
2019
entrez:
4
1
2020
pubmed:
4
1
2020
medline:
9
6
2020
Statut:
epublish
Résumé
Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles. Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC-MS/MS. Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug-drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.
Sections du résumé
BACKGROUND
BACKGROUND
Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles.
METHODS
METHODS
Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC-MS/MS.
RESULTS
RESULTS
Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D
CONCLUSIONS
CONCLUSIONS
This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug-drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.
Identifiants
pubmed: 31898492
doi: 10.1186/s12936-019-3075-5
pii: 10.1186/s12936-019-3075-5
pmc: PMC6941357
doi:
Substances chimiques
Antimalarials
0
Cytochrome P-450 Enzyme System
9035-51-2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
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