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Challenges of Using In Vitro Data for Modeling P-Glycoprotein Efflux in the Blood-Brain Barrier

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Abstract

The efficacy of central nervous system (CNS) drugs may be limited by their poor ability to cross the blood-brain barrier (BBB). Transporters, such as p-glycoprotein, may affect the distribution of many drugs into the CNS in conjunction with the restricted paracellular pathway of the BBB. It is therefore important to gain information on unbound drug concentrations in the brain in drug development to ensure sufficient drug exposure from plasma at the target site in the CNS. In vitro methods are routinely used in drug development to study passive permeability and p-glycoprotein efflux of new drugs. This review discusses the challenges in the use of in vitro data as input parameters in physiologically based pharmacokinetic (PBPK) models of CNS drug disposition of p-glycoprotein substrates. Experience with quinidine demonstrates the variability in in vitro parameters of passive permeability and active p-glycoprotein efflux. Further work is needed to generate parameter values that are independent of the model and assay. This is a prerequisite for reliable predictions of drug concentrations in the brain in vivo.

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Abbreviations

BBB:

blood-brain barrier

BCRP:

breast cancer resistance protein

BMEC:

brain microvessel endothelial cell

CLeff :

clearance related to (p-glycoprotein) efflux

CLpass :

clearance related to passive permeability

CNS:

central nervous system

CSF:

cerebrospinal fluid

Cu,brain :

unbound concentration in the brain interstitial fluid

ER:

efflux ratio

fu,brain :

unbound fraction in brain

ISF:

brain interstitial fluid

IVIVC:

in vitro—in vivo correlation

IVIVE:

in vitro—in vivo extrapolation

Km :

substrate concentration required for half-maximal transport rate

Kp,uu :

ratio of unbound drug concentrations in brain and plasma

PAMPA:

parallel artificial membrane permeability assay

Papp :

apparent permeability

PBPK:

physiologically-based pharmacokinetics

PET:

positron emission tomography

Pi :

inorganic phosphate

PK:

pharmacokinetic(s)

Ppass :

passive permeability

PS:

permeability-surface area product

QSPR:

quantitative structure-property relationship

TEER:

transendothelial electrical resistance

UWL:

unstirred water layer

Vmax :

maximal rate of transport

Vu,brain :

unbound volume of distribution in brain

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Acknowledgments and Disclosures

This work was supported by the Academy of Finland and the Pharmacy section of the FinPharma Doctoral Progam.

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  1. Kati-Sisko Vellonen

    Present address: School of Pharmacy, University of Eastern Finland, Kuopio, Finland

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  1. Division of Biopharmaceutics and Pharmacokinetics, University of Helsinki, Helsinki, Finland

    Noora Sjöstedt, Hanna Kortejärvi, Kati-Sisko Vellonen & Marjo Yliperttula

  2. Centre for Drug Research, University of Helsinki, Helsinki, Finland

    Noora Sjöstedt, Heidi Kidron & Arto Urtti

  3. Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland

    Noora Sjöstedt

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Sjöstedt, N., Kortejärvi, H., Kidron, H. et al. Challenges of Using In Vitro Data for Modeling P-Glycoprotein Efflux in the Blood-Brain Barrier. Pharm Res 31, 1–19 (2014). https://doi.org/10.1007/s11095-013-1124-2

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