A Novel Method for Preventing Non-specific Binding in Equilibrium Dialysis Assays Using Solutol® as an Additive.
J Pharm Sci
; 110(3): 1412-1417, 2021 03.
Article
em En
| MEDLINE
| ID: mdl-33248055
ABSTRACT
Accurate determination of fraction unbound in plasma is required for the interpretation of pharmacology and toxicology data, in addition to predicting human pharmacokinetics, dose, and drug-drug interaction potential. A trend, largely driven by changing target space and new chemical modalities, has increased the occurrence of compounds beyond the traditional rule of 5 physicochemical property space, meaning many drugs under development have high lipophilicity. This can present challenges for ADME assays, including non-specific binding to labware, low dynamic range and solubility. When determining unbound fraction, low recovery, due to non-specific binding, makes bioanalytical sensitivity limiting and prevents determination of free fraction for highly bound compounds. Here, mitigation of non-specific binding through the addition of 0.01% v/v of the excipient Solutol® to an equilibrium dialysis assay has been explored. Solutol® prevented non-specific binding to the dialysis membrane and showed no significant binding to plasma proteins. A test set of compounds demonstrates that this method gives comparable values of fraction unbound. In conclusion, the use of Solutol® as an additive in equilibrium dialysis formats could provide a method of mitigating non-specific binding, enabling the determination of fraction unbound values for highly lipophilic compounds.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Preparações Farmacêuticas
/
Diálise Renal
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article