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Microdialysis in CNS PKPD Research: Unraveling Unbound Concentrations

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Microdialysis in Drug Development

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 4))

Abstract

The pharmacokinetic (PK) processes of drug movements between blood and tissues and the drug concentration profiles within a tissue over time can be described with the help of microdialysis sampling. In addition, microdialysis uniquely allows measurement of the concentrations of unbound, pharmacologically active drug; it is not possible to obtain these directly with any other method. These are the most valuable outcomes of the microdialysis technique for pharmacokinetic/pharmacodynamic (PKPD) studies, and are the basis of the principles of drug distribution and PKPD in the central nervous system (CNS) presented in this chapter. This chapter will cover microdialysis studies investigating the PK and PKPD relationships of drugs in the CNS, and will also summarize alternative methods of achieving these results when microdialysis does not work or is too slow, for example in drug discovery processes.

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Abbreviations

5-OH-DPAT:

5-hydroxy-2-(N,N,-di-n-propylamino)tetralin

Atot,brain :

Total amount of drug in brain tissue per g tissue

AUC:

Area under the concentration–time curve in blood, plasma, or brain

AUCu,blood :

Unbound AUC in blood

AUCu,brain :

Unbound AUC in brain ISF

BBB:

Blood–brain barrier

BCRP:

Breast cancer resistance protein

Cblood :

Concentration of drug in blood

CLin :

Influx clearance from blood to brain across the BBB

CLout :

Efflux clearance from brain to blood across the BBB

CNS:

Central nervous system

Cu,blood :

Unbound concentration of a drug in blood

Cu,brain :

Unbound concentration of a drug in brain ISF

EC50:

Concentration resulting in half-maximal effect

ECF:

Extracellular fluid (same use as ISF here)

f u :

Fraction of unbound to total drug concentration in plasma

fu,brain :

Fraction of unbound to total drug concentration in brain tissue

GHB:

Gamma-hydroxybutyric acid

hCMEC:

Human brain endothelial capillary cell line

ISF:

Interstitial fluid (same use as ECF here)

Km:

Michaelis Menten constant (substrate concentration at half-maximal rate of metabolism)

Ki:

Equilibrium dissociation constant

K p :

Ratio of total brain to total plasma concentrations

Kp,uu :

Unbound concentration ratio between brain ISF and blood

Kp,uu,cell :

Ratio of unbound intracellular concentration (including lysosomal and other organelle distribution) to unbound ISF concentration

LC–MS/MS:

Liquid chromatography mass spectrometry

MPTP:

N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MPP+:

1-methyl-4-phenylpyridinium

NMDA:

N-methyl-D-aspartate

PET:

Positron emission tomography

P-gp:

P-glycoprotein

PD:

Pharmacodynamic

PK:

Pharmacokinetic

PKPD:

Pharmacokinetic/pharmacodynamic

pKa:

−10logKa, the acid dissociation constant

PS:

Permeability surface area product

Vblood :

Physiological volume of blood in brain per g tissue

Vu,brain :

Unbound volume of distribution in the brain, in ml × g_brain−1 tissue

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Authors and Affiliations

  1. 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. Allgemeines Krankenhaus, Department of Clinical Pharmacology, Medical University Vienna, Währinger Gürtel 18-20, Vienna, 1090, Austria

    Markus Müller

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Hammarlund-Udenaes, M. (2013). Microdialysis in CNS PKPD Research: Unraveling Unbound Concentrations. In: Müller, M. (eds) Microdialysis in Drug Development. AAPS Advances in the Pharmaceutical Sciences Series, vol 4. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4815-0_5

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