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Pharmacokinetic Concepts in Brain Drug Delivery

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Drug Delivery to the Brain

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 10))

Abstract

This chapter presents the pharmacokinetic principles of blood–brain barrier (BBB) transport and the intra-brain distribution of drugs in order to provide a basis for understanding drug delivery to the brain from a clinically relevant perspective. The most important concentrations to measure when determining drug distribution are those of the unbound drug, because it is the unbound drug that causes the pharmacological effect by interacting with the target. Therefore, this chapter also discusses the pharmacokinetic basis, the kind of information provided, and the in vivo relevance of the methods used to obtain reliable, therapeutically useful estimates of brain drug delivery. The main factors governing drug distribution to the brain are the permeability of the BBB to the drug (influx clearance), the extent of nonspecific binding to brain tissue, and the efflux clearance of the drug. The ratio of the influx and efflux clearances provides an estimation of the extent of drug equilibration across the BBB, described by K p,uu,brain. This parameter is important, as active uptake and/or efflux transporters influence the absolute brain concentrations of unbound drug in relation to those in plasma. The advantage of using K p,uu,brain during the drug discovery process lies in its ability to predict the potential success of drugs intended for action within the brain or, conversely, of those with few or no side effects in the brain.

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Abbreviations

A brain :

Amount of drug per g brain tissue excluding blood

A slice :

Amount of drug per g of brain slice

A tot.brain_inc_blood :

Amount of drug per g brain tissue including blood

AUCtot,brain :

Area under the total brain concentration–time curve

AUCtot,plasma :

Area under the total plasma concentration–time curve

AUCu,brainISF :

Area under the unbound brain ISF concentration–time curve

AUCu,plasma :

Area under the unbound plasma concentration–time curve

BBB:

Blood–brain barrier

BCSFB:

Blood–cerebrospinal fluid barrier

BBMEC:

Bovine brain microvessel endothelial cells

Caco-2:

Human epithelial colorectal adenocarcinoma cells

C buffer :

Concentration of drug in the buffer (brain slice method)

C i :

Apparent concentration of drug in a peripheral brain compartment i

C tot,blood :

Total concentration of drug in blood

C tot.plasma :

Total concentration of drug in plasma

C u,brainISF :

Concentration of drug in the brain ISF (by definition unbound)

C u,cell :

Average concentration of unbound drug in brain cells

C u,plasma :

Unbound concentration in plasma

C u,ss,plasma :

Unbound steady-state concentration in plasma

C u,ss,brainISF :

Unbound steady-state concentration in brain ISF

CLact_efflux :

Active efflux clearance from brain to blood at the BBB (ÎĽl/min/g_brain)

CLact_uptake :

Active uptake clearance from blood to brain at the BBB (ÎĽl/min/g_brain)

CLbulk_flow :

Clearance by bulk flow from brain ISF to CSF (ÎĽl/min/g_brain)

CLi :

Intercompartmental clearance between brain ISF and the peripheral brain compartment i

CLin :

Net influx clearance of drug to the brain (ÎĽl/min/g_brain), also called permeability clearance

CLmetabolism :

Metabolic clearance of drug in the brain or at the BBB (ÎĽl/min/g_brain)

CLout :

Net efflux clearance of drug from the brain (ÎĽl/min/g_brain)

CLpassive :

Passive diffusional clearance of drug at the BBB

CNS:

Central nervous system

CSF:

Cerebrospinal fluid

ECF:

Extracellular fluid in the brain (also called ISF, interstitial fluid)

f u,plasma :

Fraction of unbound drug in plasma

f u,brain :

Fraction of unbound drug in brain homogenate

f u,brain,corrected :

Fraction of unbound drug in brain homogenate after correction for pH partitioning based on the pKa(s) of the drug

f u,D :

Fraction of unbound drug in diluted brain homogenate

GI:

Gastrointestinal

ICF:

Intracellular fluid in the brain

ISF:

Interstitial fluid in the brain (also called ECF, extracellular fluid)

K i :

Inhibition constant

K in :

In situ brain perfusion unidirectional transfer constant (a clearance estimate equal to PS or CLin) (ÎĽl/min/g_brain)

K p,brain :

Partition coefficient (ratio) of total brain to total plasma drug concentrations

K p,u,brain :

Ratio of total brain drug concentration to plasma unbound drug concentration

Kp,uu,brain :

Ratio of brain ISF to plasma unbound drug concentrations

K p,uu,cell :

Ratio of brain ICF to ISF unbound drug concentrations

K p,uu,CSF :

Ratio of CSF to plasma unbound drug concentrations

logBB:

Logarithm of the ratio of total brain to total plasma drug concentrations (equal to K p)

MDCK:

Madin–Darby canine kidney cells

Mdr1:

Gene encoding for P-glycoprotein

[plasma],u/[brain],u :

Ratio of plasma to brain unbound drug concentrations

Papp :

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

PBS:

Phosphate-buffered saline

P-gp:

P-glycoprotein

PET:

Positron emission tomography

PS:

Permeability surface area product (in this context equal to net influx clearance to the brain) (ÎĽl/min/g_brain)

V blood :

Volume of blood in brain tissue

V f :

Volume of buffer film remaining around the sampled brain slice

V i :

Apparent volume of distribution of a peripheral brain compartment i

V ISF :

Physiological (and apparent) volume of ISF

V u,brain :

Volume of distribution of unbound drug in brain (ml/g_brain)

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Authors and Affiliations

  1. Translational PKPD Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden

    Margareta Hammarlund-Udenaes

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  1. Margareta Hammarlund-Udenaes
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Correspondence to Margareta Hammarlund-Udenaes .

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  1. Pharmaceutical Biosciences, Uppsala University Pharmacokinetics and Drug Therapy, Uppsala, Sweden

    Margareta Hammarlund-Udenaes

  2. LACDR/Pharmacology, Leiden University, Leiden, The Netherlands

    Elizabeth C.M. de Lange

  3. Pharmaceutical Sciences Division, University of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin, USA

    Robert G. Thorne

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Hammarlund-Udenaes, M. (2014). Pharmacokinetic Concepts in Brain Drug Delivery. In: Hammarlund-Udenaes, M., de Lange, E., Thorne, R. (eds) Drug Delivery to the Brain. AAPS Advances in the Pharmaceutical Sciences Series, vol 10. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9105-7_5

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