Efflux transporters in the blood–brain interfaces –<i>in vitro</i>and<i>in vivo</i>methods and correlations

Krajcsi, Péter; Jani, Márton; Töth, Beáta; Kis, Emese; Beéry, Erzsébet; Sziráki, István

doi:10.1517/17425255.2012.668184

Cited by 15 publications

(8 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…; Krajcsi et al . ). For example, intracerebral microdialysis using quinidine as a selective P‐gp substrate has been utilized to investigate P‐gp function at the rat BBB (Liu et al .…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

In vivo induction of P‐glycoprotein expression at the mouse blood–brain barrier: an intracerebral microdialysis study

Chan

Saldivia²,

Yang³

et al. 2013

Journal of Neurochemistry

View full text Add to dashboard Cite

Intracerebral microdialysis was utilized to investigate the effect of P-glycoprotein (a drug efflux transporter) induction at the mouse blood-brain barrier (BBB) on brain extracellular fluid concentrations of quinidine, an established substrate of P-glycoprotein. Induction was achieved by treating male CD-1 mice for 3 days with 5 mg/kg/day dexamethasone (DEX), a ligand of the nuclear receptor, pregnane X receptor, and a P-glycoprotein inducer. Tandem liquid chromatography mass spectrometric method was used to quantify analytes in dialysate, blood and plasma. P-glycoprotein, pregnane X receptor and Cyp3a11 (metabolizing enzyme for quinidine) protein expression in capillaries and brain homogenates was measured by immunoblot analysis. Following quinidine i.v. administration, the average ratio of unbound quinidine concentrations in brain extracellular fluid (determined from dialysate samples) to plasma at steady state (375-495 min) or K p, uu, ECF/Plasma in the DEX-treated animals was 2.5-fold lower compared with vehicle-treated animals. In DEX-treated animals, P-glycoprotein expression in brain capillaries was 1.5-fold higher compared with vehicle-treated animals while Cyp3a11 expression in brain capillaries was not significantly different between the two groups. These data demonstrate that P-gp induction mediated by DEX at the BBB can significantly reduce quinidine brain extracellular fluid concentrations by decreasing its brain permeability and further suggest that drug-drug interactions as a result of P-gp induction at the BBB are possible.

show abstract

“…; Krajcsi et al . ). For example, intracerebral microdialysis using quinidine as a selective P‐gp substrate has been utilized to investigate P‐gp function at the rat BBB (Liu et al .…”

Section: Discussionmentioning

confidence: 97%

“…With the use of selective drug transporter substrates such as the antiarrhythmic drug quinidine, this technique has been utilized in rats to examine the role of P‐gp at the BBB in vivo (Krajcsi et al . ; Syvänen et al . ; Westerhout et al .…”

mentioning

confidence: 99%

In vivo induction of P‐glycoprotein expression at the mouse blood–brain barrier: an intracerebral microdialysis study

Chan

Saldivia²,

Yang³

et al. 2013

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…On the contrary, rats and mice are ubiquitous, well-established small laboratory animals, readily available to most labs worldwide. Mice also display another advantage over human models as several genetically-modified mice have already been produced, including humanized mice expressing human transporters [20]. Due to their rapid reproduction and maturation to adulthood, they are both good choice models to retrieve primary cells.…”

Section: Introductionmentioning

confidence: 99%

IVIVC Assessment of Two Mouse Brain Endothelial Cell Models for Drug Screening

et al. 2019

View full text Add to dashboard Cite

Since most preclinical drug permeability assays across the blood-brain barrier (BBB) are still evaluated in rodents, we compared an in vitro mouse primary endothelial cell model to the mouse b.End3 and the acellular parallel artificial membrane permeability assay (PAMPA) models for drug screening purposes. The mRNA expression of key feature membrane proteins of primary and bEnd.3 mouse brain endothelial cells were compared. Transwell® monolayer models were further characterized in terms of tightness and integrity. The in vitro in vivo correlation (IVIVC) was obtained by the correlation of the in vitro permeability data with log BB values obtained in mice for seven drugs. The mouse primary model showed higher monolayer integrity and levels of mRNA expression of BBB tight junction (TJ) proteins and membrane transporters (MBRT), especially for the efflux transporter Pgp. The IVIVC and drug ranking underlined the superiority of the primary model (r2 = 0.765) when compared to the PAMPA-BBB (r2 = 0.391) and bEnd.3 cell line (r2 = 0.019) models. The primary monolayer mouse model came out as a simple and reliable candidate for the prediction of drug permeability across the BBB. This model encompasses a rapid set-up, a fair reproduction of BBB tissue characteristics, and an accurate drug screening.

show abstract

“…Thus, P-gp and BCRP have an important function in brain. It has been reported that compounds with P app(AP?BL) > 3 Â 10 À6 cm/s easily penetrate the brain, while compounds with P app(AP?BL) < 1 Â 10 À6 -cm/s are unable to pass across the BBB [45]. Our studies showed that P app(AP?BL) values of GA (C15:1) and GA (C17:1) in the MDCK-MDR1 cells were both in the range from 1 Â 10 À6 cm/s to 3 Â 10 À6 cm/s, indicating that GA (C15:1) and GA (C17:1) are hard to penetrate the BBB.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin A affects the bioavailability of ginkgolic acids via inhibition of P-gp and BCRP

Yao

et al. 2014

European Journal of Pharmaceutics and Biopharmaceutics

View full text Add to dashboard Cite

Efflux transporters in the blood–brain interfaces –in vitroandin vivomethods and correlations

Cited by 15 publications

References 96 publications

In vivo induction of P‐glycoprotein expression at the mouse blood–brain barrier: an intracerebral microdialysis study

In vivo induction of P‐glycoprotein expression at the mouse blood–brain barrier: an intracerebral microdialysis study

IVIVC Assessment of Two Mouse Brain Endothelial Cell Models for Drug Screening

Cyclosporin A affects the bioavailability of ginkgolic acids via inhibition of P-gp and BCRP

Contact Info

Product

Resources

About