Impact of In Vitro Passive Permeability in a P-gp-transfected LLC-PK1 Model on the Prediction of the Rat and Human Unbound Brain-to-Plasma Concentration Ratio

Nicolaï, Johan; Chapy, Hélène; Gillent, Eric; Saunders, Kenneth; Ungell, Anna‐Lena; Nicolas, Jean‐Marie; Chanteux, Hugues

doi:10.1007/s11095-020-02867-z

Cited by 12 publications

(9 citation statements)

References 59 publications

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“…In this study, we predicted static K p,uu,brain as well as dynamic ISF concentrations from in vitro data using the REF approach. Although the static predictions were conducted as described before, 9–11,28 our study can be distinguished from these previous studies in several ways. First, the compounds used for verification of our approach are selective P‐gp substrates 29–32 .…”

Section: Discussionmentioning

confidence: 99%

Successful Prediction of Human Steady‐State Unbound Brain‐to‐Plasma Concentration Ratio of P‐gp Substrates Using the Proteomics‐Informed Relative Expression Factor Approach

Storelli

Anoshchenko

Unadkat

2021

Clin Pharma and Therapeutics

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Accurately predicting unbound brain interstitial fluid (ISF) concentrations of CNS drugs is challenging, especially when drugs are substrates of efflux transporters (e.g., P-glycoprotein). This is one reason why development of CNS drugs has a high attrition rate. WHAT QUESTION DID THIS STUDY ADDRESS?  We determined whether the proteomics-informed relative expression factor (REF) approach can successfully predict the unbound human brain ISF distribution of drugs at steady state or pseudoequilibrium.

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Section: Discussionmentioning

confidence: 99%

Successful Prediction of Human Steady‐State Unbound Brain‐to‐Plasma Concentration Ratio of P‐gp Substrates Using the Proteomics‐Informed Relative Expression Factor Approach

Storelli

Anoshchenko

Unadkat

2021

Clin Pharma and Therapeutics

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“…The use of in vitro cell culture data to estimate brain drug disposition has also been addressed in other studies. Recently Nikolai et al and Storelli et al have effectively predicted human K p,uu,brain using PBPK models coupled with inputs from conventional in vitro permeability assays, and transporter proteomics [ 38 , 14 ]. However, only few studies have attempted to create an in vitro setup that enables estimation of drug distribution parameters such as K p,brain and K p,uu,brain .…”

Section: Discussionmentioning

confidence: 99%

Application of a new MDCKII-MDR1 cell model to measure the extent of drug distribution in vitro at equilibrium for prediction of in vivo unbound brain-to-plasma drug distribution

Langthaler,

Jones,

Saaby

et al. 2024

Fluids Barriers CNS

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Intro: Reliable estimates of drug uptake from blood to brain parenchyma are crucial in CNS drug discovery and development. While in vivo Kp,uu,brain estimates are the gold standard for investigating brain drug disposition, animal usage is a limitation to high throughput application. This study investigates an in vitro model using P-gp expressing MDCKII-MDR1 cells for predicting in vivo brain drug penetration. Methods: In vitro equilibrium distribution studies were conducted in apical and basolateral solutions with high protein content to estimate Kp,brain and Kp,uu,brain values. The correlation between in vitro and in vivo Kp,brain values for a set of compounds was examined. Results: We observed a good correlation between in vitro and in vivo Kp,brain values (R2 = 0.69, Slope: 1.6), indicating that the in vitro model could predict in vivo drug brain penetration. The ‘unilateral (Uni-L)’ in vitro setup correctly classified 5 out of 5 unrestricted compounds and 3 out of 5 restricted compounds. Possible reasons for the observed disparities for some compounds have been discussed, such as difference in transport areas between in vitro and in vivo settings and effect of pH changes. Conclusion: The in vitro assay setup developed in this study holds promise for predicting in vivo drug brain penetration in CNS drug discovery. The correlation between in vitro and in vivo Kp,brain values, underscores that the model may have potential for early-stage screening. With minor refinements, this in vitro approach could reduce the reliance on in vivo experiments, accelerating the pace of CNS drug discovery and promoting a more ethical research approach.

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“…The use of in vitro cell culture data to estimate brain drug disposition has also been addressed in other studies. Recently Nikolai et al and Storelli et al have effectively predicted human K p,uu,brain using PBPK models coupled with inputs from conventional in vitro permeability assays, and transporter proteomics (Nicolai et al 2020;Storelli et al 2021). However, only few studies have attempted to create an in vitro setup that enables estimation of drug distribution parameters such as K p,brain and K p,uu,brain .…”

Section: Discussionmentioning

confidence: 99%

Application of a new MDCKII-MDR1 cell model to measure the extent of drug distribution in vitro at equilibrium for prediction of in vivo unbound brain-to-plasma drug distribution.

Langthaler,

Jones,

Saaby

et al. 2023

Preprint

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Intro: Reliable estimates of drug uptake from blood to brain parenchyma are crucial in CNS drug discovery and development. While in vivo Kp,uu,brain estimates are the gold standard for investigating brain drug disposition, animal usage is a limitation to high throughput application. This study investigates an in vitro model using P-gp expressing MDCKII-MDR1 cells for predicting in vivo brain drug penetration. Methods: In vitro equilibrium distribution studies were conducted in apical and basolateral solutions with high protein content to estimate Kp,brain and Kp,uu,brain values. The correlation between in vitro and in vivo Kp,brain values for a set of compounds was examined. Results: We observed a good correlation between in vitro and in vivo Kp,brain values (R2=0.69, Slope: 1.6), indicating that the in vitro model could predict in vivo drug brain penetration. The ‘Uni-L’ in vitro setup correctly classified 5 out of 5 unrestricted compounds and 3 out of 5 restricted compounds. Possible reasons for the observed disparities for some compounds have been discussed, such as difference in transport areas between in vitro and in vivo settings and effect of pH changes. Conclusion: The in vitro assay setup developed in this study holds promise for predicting in vivo drug brain penetration in CNS drug discovery. The correlation between in vitro and in vivo Kp,brain values, underscores that the model may have potential for early-stage screening. With minor refinements, this in vitro approach could reduce the reliance on in vivo experiments, accelerating the pace of CNS drug discovery and promoting a more ethical research approach.

show abstract

Impact of In Vitro Passive Permeability in a P-gp-transfected LLC-PK1 Model on the Prediction of the Rat and Human Unbound Brain-to-Plasma Concentration Ratio

Cited by 12 publications

References 59 publications

Successful Prediction of Human Steady‐State Unbound Brain‐to‐Plasma Concentration Ratio of P‐gp Substrates Using the Proteomics‐Informed Relative Expression Factor Approach

Successful Prediction of Human Steady‐State Unbound Brain‐to‐Plasma Concentration Ratio of P‐gp Substrates Using the Proteomics‐Informed Relative Expression Factor Approach

Application of a new MDCKII-MDR1 cell model to measure the extent of drug distribution in vitro at equilibrium for prediction of in vivo unbound brain-to-plasma drug distribution

Application of a new MDCKII-MDR1 cell model to measure the extent of drug distribution in vitro at equilibrium for prediction of in vivo unbound brain-to-plasma drug distribution.

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