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Drug Discovery Methods for Studying Brain Drug Delivery and Distribution

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Drug Delivery to the Brain

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 33))

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Abstract

Methods used in drug discovery laboratories for assessing the delivery of small molecules to the brain have changed significantly in recent years. There is now more focus on measuring or estimating target unbound drug concentrations in the brain and evaluating the quantitative aspects of drug transport across the blood-brain barrier (BBB). The techniques for the investigation of the rate and extent of BBB transport of new chemical entities (NCEs) are discussed in this chapter. Combinatory methodology for rapid mapping of the extent of brain drug delivery via assessment of the unbound drug brain partitioning coefficient is presented. The chapter also explains the procedures for approximation of subcellular distribution of NCEs, particularly into the lysosomes. The principles, technical issues, advantages, and potential applications of techniques for evaluation of intra-brain distribution, i.e., equilibrium dialysis-based brain homogenate and brain slice methods, are described. The assessment of the extent of BBB transport and intracellular distribution of NCEs, the identification of intra-brain distribution patterns, and their integration with pharmacodynamic measurements are valuable implements for candidate evaluation and selection in drug discovery and development.

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Abbreviations

A brain :

Amount of drug in brain tissue

AUCtot,brain:

Area under the total brain concentration-time curve

AUCtot,plasma:

Area under the total plasma concentration-time curve

BBB:

Blood-brain barrier

BCRP:

Breast cancer resistance-associated protein

BCSFB:

Blood-CSF barrier

CB:

Cellular barrier

C buffer :

Concentration of compound in the buffer (brain slice method)

C tot,blood :

Total drug concentration in blood

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

C tot,plasma :

Total drug concentration in plasma

Ctot,brain:

Total drug concentration in brain

Cu,brainISF:

Unbound drug concentration in brain interstitial fluid

Cu,cell:

Unbound drug concentration in intracellular fluid

Cu,cyto:

Unbound drug concentration in cytosol

Cu,lyso:

Unbound drug concentration in lysosomes

C u,plasma :

Unbound drug concentration in plasma

DMPK:

Drug metabolism and pharmacokinetics

ECF:

Extracellular fluid (same as ISF)

ED:

Equilibrium dialysis

ER:

Efflux ratio

f u,brain :

Fraction of unbound drug in brain homogenate

f u,brain,corrected :

fu,brain corrected for pH partitioning into cells

f u,hD :

Fraction of unbound drug in diluted brain homogenate

f u,plasma :

Fraction of unbound drug in plasma

HTS:

High-throughput screening

ICF:

Intracellular fluid in the brain

ISF:

Interstitial fluid in the brain

K d :

Equilibrium dissociation constant

Kp,brain:

Ratio of total-brain-to-total plasma drug concentrations (also abbreviated as BB)

Kp,uu,brain:

Ratio of brain ISF-to-plasma unbound drug concentrations

Kp,uu,cell:

Ratio of brain ICF-to-ISF unbound drug concentrations

Kp,uu,cyto:

Ratio of cytosolic-to-extracellular unbound drug concentrations

K p,uu,lyso :

Ratio of lysosomic-to-cytosolic unbound drug concentrations

LC-MS/MS:

Liquid chromatography tandem mass spectrometry

logBB:

Logarithm of Kp,brain (BB)

MWCO:

Molecular weight cut-off

NCE:

New chemical entity

neuroPK:

Neuropharmacokinetics

Papp:

Unidirectional apparent permeability coefficient measured in the apical-to-basolateral direction (cm/s)

PBS:

Phosphate-buffered saline

PD:

Pharmacodynamics

PET:

Positron emission tomography

P-gp:

P-glycoprotein

PK:

Pharmacokinetics

PLD:

Drug-induced phospholipidosis

PS:

Permeability surface area product (μL/min · g brain−1)

V ss :

Apparent volume of distribution at steady state

V u,brain :

Volume of distribution of unbound drug in brain (mL · g brain−1)

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Authors and Affiliations

  1. Translational PKPD Research Group, Department of Pharmacy, Uppsala University, Uppsala, Sweden

    Irena Loryan & Margareta Hammarlund-Udenaes

  2. SciLife Lab, Solna, Sweden

    Irena Loryan & Margareta Hammarlund-Udenaes

Authors
  1. Irena Loryan
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  2. Margareta Hammarlund-Udenaes
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Correspondence to Irena Loryan .

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Editors and Affiliations

  1. Research Division of Systems Pharmacology and Pharmacy, Leiden University, Leiden, The Netherlands

    Elizabeth C.M. de Lange

  2. Department of Pharmacy, Uppsala University, Uppsala, Sweden

    Margareta Hammarlund-Udenaes

  3. Biology Discovery, Denali Therapeutics, South San Francisco, CA, USA

    Robert G. Thorne

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Loryan, I., Hammarlund-Udenaes, M. (2022). Drug Discovery Methods for Studying Brain Drug Delivery and Distribution. In: de Lange, E.C., Hammarlund-Udenaes, M., Thorne, R.G. (eds) Drug Delivery to the Brain. AAPS Advances in the Pharmaceutical Sciences Series, vol 33. Springer, Cham. https://doi.org/10.1007/978-3-030-88773-5_13

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