Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood–brain barriers studied with R-11Cverapamil positron emission tomographyReportar como inadecuado

Pharmacokinetic modeling of P-glycoprotein function at the rat and human blood–brain barriers studied with R-11Cverapamil positron emission tomography - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

EJNMMI Research

, 2:58

First Online: 16 October 2012Received: 30 August 2012Accepted: 26 September 2012


BackgroundThis study investigated the influence of P-glycoprotein P-gp inhibitor tariquidar on the pharmacokinetics of P-gp substrate radiotracer R-Cverapamil in plasma and brain of rats and humans by means of positron emission tomography PET.

MethodsData obtained from a preclinical and clinical study, in which paired R-Cverapamil PET scans were performed before, during, and after tariquidar administration, were analyzed using nonlinear mixed effects NLME modeling. Administration of tariquidar was included as a covariate on the influx and efflux parameters Qin and Qout in order to investigate if tariquidar increased influx or decreased outflux of radiotracer across the blood–brain barrier BBB. Additionally, the influence of pilocarpine-induced status epilepticus SE was tested on all model parameters, and the brain-to-plasma partition coefficient VT-NLME was calculated.

ResultsOur model indicated that tariquidar enhances brain uptake of R-Cverapamil by decreasing Qout. The reduction in Qout in rats during and immediately after tariquidar administration sevenfold was more pronounced than in the second PET scan acquired 2 h after tariquidar administration fivefold. The effect of tariquidar on Qout in humans was apparent during and immediately after tariquidar administration twofold reduction in Qout but was negligible in the second PET scan. SE was found to influence the pharmacological volume of distribution of the central brain compartment Vbr1. Tariquidar treatment lead to an increase in VT-NLME, and pilocarpine-induced SE lead to increased R-Cverapamil distribution to the peripheral brain compartment.

ConclusionsUsing NLME modeling, we were able to provide mechanistic insight into the effects of tariquidar and SE on R-Cverapamil transport across the BBB in control and 48 h post SE rats as well as in humans.

KeywordsNonlinear mixed effects modeling Positron emission tomography R-Cverapamil P-glycoprotein Tariquidar Pilocarpine-induced epilepsy Species differences Abbreviations2T4KTwo tissue compartment model

BBBBlood–brain barrier

CerCerebellum region

CLSystemic clearance

CSCorpus striatum region

ECEntorhinal cortex region

EffscanEffect of scan 2 as a fractional change from scan 1

EffSEEffect of pilocarpine-induced SE as a fractional change from control

EfftariquidarEffect of tariquidar treatment as a fractional change from no treatment

FMCFrontal motor cortex region

NLMENonlinear mixed effects

OFVObjective function value


PETPositron emission tomography



Q1Clearance from central compartment to first peripheral compartment

Q2Clearance from central compartment to second peripheral compartment

QinClearance from plasma to brain

QoutClearance from brain to plasma

SEStatus epilepticus

ShippSeptal hippocampus region

SUVStandardized uptake value

ThThalamus region

THippTemporal hippocampus region

Vbr1Pharmacological distribution volume in first brain compartment

Vbr2Pharmacological distribution volume in second brain compartment

VcPharmacological distribution volume in central compartment

Vp1Pharmacological distribution volume in first peripheral compartment

Vp2Pharmacological distribution volume in second peripheral compartment

VT-LoganThe brain-to-plasma partition coefficient obtained with Logan analysis

VT-NLMEThe brain-to-plasma partition coefficient obtained with NLME

VT-2T4KThe brain-to-plasma partition coefficient obtained with 2T4K

WBWhole brain region.

Electronic supplementary materialThe online version of this article doi:10.1186-2191-219X-2-58 contains supplementary material, which is available to authorized users.

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Autor: Julia Müllauer - Claudia Kuntner - Martin Bauer - Jens P Bankstahl - Markus Müller - Rob A Voskuyl - Oliver Langer - St


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