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Drug Distribution Part 2. Predicting Volume of Distribution from Plasma Protein Binding and Membrane Partitioning.

ABSTRACT: Volume of distribution is an important pharmacokinetic parameter in the distribution and half-life of a drug. Protein binding and lipid partitioning together determine drug distribution.Here we present a simple relationship that estimates the volume of distribution with the fraction of drug unbound in both plasma and microsomes. Model equations are based upon a two-compartment system and the experimental fractions unbound in plasma and microsomes represent binding to plasma proteins and cellular lipids, respectively.The protein and lipid binding components were parameterized using a dataset containing human in vitro and in vivo parameters for 63 drugs. The resulting equation explains ~84% of the variance in the log of the volume of distribution with an average fold-error of 1.6, with 3 outliers.These results suggest that Vss can be predicted for most drugs from plasma protein binding and microsomal partitioning.

SUBMITTER: Korzekwa K

PROVIDER: S-EPMC5285473 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Drug Distribution Part 2. Predicting Volume of Distribution from Plasma Protein Binding and Membrane Partitioning.

Korzekwa Ken K Nagar Swati S

Pharmaceutical research 20161213 3

<h4>Purpose</h4>Volume of distribution is an important pharmacokinetic parameter in the distribution and half-life of a drug. Protein binding and lipid partitioning together determine drug distribution.<h4>Methods</h4>Here we present a simple relationship that estimates the volume of distribution with the fraction of drug unbound in both plasma and microsomes. Model equations are based upon a two-compartment system and the experimental fractions unbound in plasma and microsomes represent binding ...[more]

PMID: 27966088

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Project description:BackgroundMany integral membrane proteins, like their non-membrane counterparts, form either transient or permanent multi-subunit complexes in order to carry out their biochemical function. Computational methods that provide structural details of these interactions are needed since, despite their importance, relatively few structures of membrane protein complexes are available.ResultsWe present a method for predicting which residues are in protein-protein binding sites within the transmembrane regions of membrane proteins. The method uses a Random Forest classifier trained on residue type distributions and evolutionary conservation for individual surface residues, followed by spatial averaging of the residue scores. The prediction accuracy achieved for membrane proteins is comparable to that for non-membrane proteins. Also, like previous results for non-membrane proteins, the accuracy is significantly higher for residues distant from the binding site boundary. Furthermore, a predictor trained on non-membrane proteins was found to yield poor accuracy on membrane proteins, as expected from the different distribution of surface residue types between the two classes of proteins. Thus, although the same procedure can be used to predict binding sites in membrane and non-membrane proteins, separate predictors trained on each class of proteins are required. Finally, the contribution of each residue property to the overall prediction accuracy is analyzed and prediction examples are discussed.ConclusionGiven a membrane protein structure and a multiple alignment of related sequences, the presented method gives a prioritized list of which surface residues participate in intramembrane protein-protein interactions. The method has potential applications in guiding the experimental verification of membrane protein interactions, structure-based drug discovery, and also in constraining the search space for computational methods, such as protein docking or threading, that predict membrane protein complex structures.

Dataset Information

Drug Distribution Part 2. Predicting Volume of Distribution from Plasma Protein Binding and Membrane Partitioning.

Publications

Drug Distribution Part 2. Predicting Volume of Distribution from Plasma Protein Binding and Membrane Partitioning.

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