Prediction of Volume of Distribution Values in Humans for Neutral and Basic Drugs Using Physicochemical Measurements and Plasma Protein Binding Data

2002 ◽  
Vol 45 (13) ◽  
pp. 2867-2876 ◽  
Author(s):  
Franco Lombardo ◽  
R. Scott Obach ◽  
Marina Y. Shalaeva ◽  
Feng Gao
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Volume Of Distribution ◽  
Basic Drugs ◽  
Binding Data ◽  
Neutral And Basic Drugs ◽  
Physicochemical Measurements

Plasma protein binding of basic drugs

1977 ◽  
Vol 22 (5part1) ◽  
pp. 539-544 ◽  
Author(s):  
Olof Borgai ◽  
Kenneth M. Piafsky ◽  
Odd G. Nilsen
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Basic Drugs

scholarly journals Quantitative Structure – Pharmacokinetics Relationships for Plasma Protein Binding of Basic Drugs

2017 ◽  
Vol 20 (1) ◽  
pp. 349 ◽  
Author(s):  
Zvetanka Dobreva Zhivkova
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Geometric Mean ◽  
External Validation ◽  
Molecular Volume ◽  
Basic Drugs ◽  
Quantitative Structure ◽  
Chemical Structures ◽  
Very High

Purpose. Binding of drugs to plasma proteins is a common physiological occurrence which may have a profound effect on both pharmacokinetics and pharmacodynamics. The early prediction of plasma protein binding (PPB) of new drug candidates is an important step in drug development process. The present study is focused on the development of quantitative structure – pharmacokinetics relationship (QSPkR) for the negative logarithm of the free fraction of the drug in plasma (pfu) of basic drugs. Methods. A dataset includes 220 basic drugs, which chemical structures are encoded by 176 descriptors.  Genetic algorithm, stepwise regression and multiple linear regression are used for variable selection and model development. Predictive ability of the model is assessed by internal and external validation.  Results. A simple, significant, interpretable and predictive QSPkR model is constructed for pfu of basic drugs. It is able to predict 59% of the drugs from an external validation set within the 2-fold error of the experimental values with squared correlation coefficient of prediction 0.532, geometric mean fold error (GMFE) 1.94 and mean absolute error (MAE) 0.17. Conclusions. PPB of basic drugs is favored by the lipophilicity, the presence of aromatic C-atoms (either non-substituted, or involved in bridged aromatic systems) and molecular volume.  The fraction ionized as a base fB and the presence of quaternary C-atoms contribute negatively to PPB. A short checklist of criteria for high PPB is defined, and an empirical rule for distinguishing between low, high and very high plasma protein binders is proposed based. This rule allows correct classification of 69% of the very high binders, 71% of the high binders and 91% of the low binders in plasma. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Species differences in drug plasma protein binding

MedChemComm ◽  
2014 ◽  
Vol 5 (7) ◽  
pp. 963-967 ◽  
Author(s):  
Nicola Colclough ◽  
Linette Ruston ◽  
J. Matthew Wood ◽  
Philip A. MacFaul
Keyword(s):  
Drug Discovery ◽  
Protein Binding ◽  
Human Plasma ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Plasma Proteins ◽  
Species Differences ◽  
Human Plasma Protein ◽  
Binding Data ◽  
Drug Plasma

Comparison of the human plasma protein binding data for a variety of drug discovery compounds indicates that compounds tend to be slightly more bound to human plasma proteins, than compared to plasma proteins from rats, dogs or mice.

Cremophor EL Alters the Plasma Protein Binding and Pharmacokinetic Profile of Valspodar in Rats

Drug Research ◽  
2017 ◽  
Vol 67 (10) ◽  
pp. 591-595
Author(s):  
Ziyad Binkhathlan
Keyword(s):  
Protein Binding ◽  
Plasma Protein Binding ◽  
Plasma Protein ◽  
Pharmaceutical Formulations ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Cremophor El ◽  
Unbound Fraction ◽  
Peg 400

AbstractCremophor EL is a nonionic surfactant widely used in pharmaceutical formulations. Nonetheless, there are several reports on the influence of this excipient on the protein binding, pharmacokinetics, and pharmacodynamics of drugs. Valspodar is an investigational non-immunosuppressive derivative of cyclosporine A, used in clinical trials for treatment of multidrug resistant tumors. The formulation of valspodar (Amdray®) contains cremophor EL and ethanol as solubilizing agents. The main aim of the current study was to assess the plasma protein binding (in vitro) and the pharmacokinetic profile of valspodar in the cremophor EL-based formulation in comparison to a cremophor EL-free formulation following intravenous (i. v.) administration to rats. Valspodar dissolved in PEG 400/ethanol (diluted in Dextrose 5%) was used as the cremophor EL-free formulation. The in vitro plasma unbound fraction (f u) of valspodar in the cremophor EL formulation was 2.3-fold higher than the PEG 400/ethanol formulation. Following a single i. v. dose of 5 mg/kg, valspodar in the cremophor EL-based formulation had around 50% lower plasma AUC compared to the PEG 400/ethanol formulation. Moreover, the cremophor EL formulation had significantly higher volume of distribution and clearance in comparison to the PEG 400-based formulation. The results highlight the significance of excipient-drug interaction that should not be overlooked during the early stages of drug development.

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