PCA

Estimate unbound fraction of drugs
Principal component analysis (n=2)

ElasticNet: Linear regression

1159 drugs x 28 variables obtained by RDkit & Chemaxon.

fup = f( logP, logS, polarity, pKa, hlb, aromaticity ....) = f( PC1(36.5%), PC2(20.3%) ); PC1+PC2 accounts for 56.8% variance

Metabolic Flux

Drug metabolism pathway visualized by escher git map.

Use linear optimization with constraints to estimate metabolic fluxes of drugs .

Combine FBA ( flux balance analysis) and PBPK to characterize drug metabolism in hepatocytes.

Genotype Variation

Variants of SLCO1B1, ABCG2, and ABCC2 etc. will cause variations on parameters related to drug absorption, cellular uptake and clearance.
SLCO family transporters: absorption, hepatocyte uptake
ABCG family transporter: biliary clearance, bile duct
CYP family enzymes: oxidative reactions (O2, NADPH)

Next Generation Physiology Based Pharmacokinetic Model

Qingyang Wang,Sizhe Qiu, Sinha Parnal, Xiaoke Bi

Mentor: Dr. Daniel Zielinski

Project Explanation

Group01_2020_PBPK.mp4

Acknowledgements: We would like to acknowledge Dr. Zielinski for his tutelage, discretion and overall guidance with respect to this project in its entirety. Furthermore, we would like to provide Dr. Bernhard O. Palsson special thanks for his continued direction throughout the whole project. Along with our mentors, special acknowledgements also go out to our Teaching Assistants for ensuring the project was completed in a timely manner and for their continued counsel throughout the project. Finally, we would like to thank Dr. Wheeler for his continued tutelage, direction and guidance for this project - without his guidance, this project would not have been possible.

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