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Pharmacokinetic Consequences of Active Drug Efflux at the Blood–Brain Barrier

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Purpose

The objective of this simulation study was to investigate how the nature, location, and capacity of the efflux processes in relation to the permeability properties influence brain concentrations.

Methods

Reduced brain concentrations can be due to either influx hindrance, a gatekeeper function in the luminal membrane, which has been suggested for ABCB1 (P-glycoprotein), or efflux enhancement by transporters that pick up molecules on one side of the luminal or abluminal membrane and release them on the other side. Pharmacokinetic models including passive transport, influx hindrance, and efflux enhancement were built using the computer program MATLAB. The simulations were based on experimentally obtained parameters for morphine, morphine-3-glucuronide, morphine-6-glucuronide, and gabapentin.

Results

The influx hindrance process is the more effective for keeping brain concentrations low. Efflux enhancement decreases the half-life of the drug in the brain, whereas with influx hindrance the half-life is similar to that seen with passive transport. The relationship between the influx and efflux of the drug across the blood–brain barrier determines the steady-state ratio of brain to plasma concentrations of unbound drug, K p,uu .

Conclusions

Both poorly and highly permeable drugs can reach the same steady-state ratio, although the time to reach steady state will differ. The volume of distribution of unbound drug in the brain does not influence K p,uu , but does influence the total brain-to-blood ratio K p and the time to reach steady state in the brain.

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Abbreviations

ABCB1:

P-glycoprotein

A tot,br :

total (unbound, bound, intracellular) amount of drug in the brain

BBB:

blood–brain barrier

CL :

systemic clearance

CL pass :

unbound passive clearance

CL 1 :

clearance by influx hindrance

CL 2 :

clearance by efflux enhancement at the luminal membrane

CL 3 :

clearance by efflux enhancement at the abluminal membrane

CNS:

central nervous system

CSF:

cerebrospinal fluid

C bl :

drug concentration in blood

CL in :

net influx clearance

CL out :

net efflux clearance

C u,bl :

unbound drug concentration in blood

C u,br :

unbound drug concentration in brain

C u,ec :

unbound drug concentration in endothelium

C u,ss,bl :

unbound drug concentration in blood at steady state

C u,ss,br :

unbound drug concentration in brain at steady state

ISF:

interstitial fluid

J max :

maximal active transport capacity elimination constant

k el :

elimination constant

K p :

ratio of total brain to total plasma concentration

K p,u :

ratio of total brain to unbound plasma concentration

K p,uu :

ratio of unbound brain to unbound plasma concentration

K t :

unbound concentration at 50% of Jmax

M3G:

morphine-3-glucuronide

M6G:

morphine-6-glucuronide

OAT3:

organic anion transporter

Pgp:

P-glycoprotein

PS:

permeability surface area

Q :

mass flux

R 0 :

infusion rate

t 1/2 :

half-life

V bl :

volume of blood in the brain tissue

V u,bl :

distribution volume of unbound drug in blood

V u,br :

distribution volume of unbound drug in brain

V u,ec :

distribution volume of unbound drug in endothelium

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Acknowledgments

This work was supported by the Swedish foundation for strategic research (Stockholm, Sweden), by the Swedish Research Council no 11558, and by Uppsala Imanet (Uppsala, Sweden).

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Author notes

  1. Selma Sahin

    Present address: Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey

Authors and Affiliations

  1. Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24, Uppsala, Sweden

    Stina Syvänen, Rujia Xie, Selma Sahin & Margareta Hammarlund-Udenaes

  2. Uppsala Imanet, Box 967, 751 09, Uppsala, Sweden

    Stina Syvänen

  3. Pfizer Inc, Sandwich, UK

    Rujia Xie

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  1. Stina Syvänen
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  2. Rujia Xie
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Correspondence to Margareta Hammarlund-Udenaes.

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Syvänen, S., Xie, R., Sahin, S. et al. Pharmacokinetic Consequences of Active Drug Efflux at the Blood–Brain Barrier. Pharm Res 23, 705–717 (2006). https://doi.org/10.1007/s11095-006-9780-0

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