Effects of pluronic P85 on GLUT1 and MCT1 transporters in the blood-brain barrier.
OBJECTIVE
The amphiphilic block copolymer Pluronic P85 (P85) increases the permeability of the blood-brain barrier (BBB) with respect to a broad spectrum of drugs by inhibiting the drug efflux transporter, P-glycoprotein (Pgp). In this regard, P85 serves as a promising component for CNS drug delivery systems. To assess the possible effects of P85 on other transport systems located in the brain, we examined P85 interactions with the glucose (GLUT1) and monocarboxylate (MCT1) transporters.


METHODS
Polarized monolayers of primary cultured bovine brain microvessel endothelial cells (BBMEC) were used as an in vitro model of the BBB. 3H-2-deoxy-glucose and 14C-lactate were selected as GLUT1 and MCT1 substrates, respectively. The accumulation and flux of these substrates added to the luminal side of the BBMEC monolayers were determined.


RESULTS
P85 has little effect on 3H-2-deoxy-glucose transport. However, a significant decrease 14C-lactate transport across BBMEC monolayers is observed. Histology, immunohistochemistry, and enzyme histochemistry studies show no evidence of P85 toxicity in liver, kidney, and brain in mice.


CONCLUSIONS
This study suggests that P85 formulations do not interfere with the transport of glucose. This is, probably, due to compensatory mechanisms in the BBB. Regarding the transport of monocarboxylates, P85 formulations might slightly affect their homeostasis in the brain, however, without any significant toxic effects.
Batrakova
Elena V
EV
College of Pharmacy, Department of Pharmaceutical Sciences, Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Zhang
Yan
Y
Li
Yili
Y
Li
Shu
S
Vinogradov
Sergei V
SV
Persidsky
Y
Y
Alakhov
Valery Yu
VY
Miller
Donald W
DW
Kabanov
Alexander V
AV
D000818:Animals; D000963:Antimetabolites / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D002469:Cell Separation; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005079:Excipients; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D051272:Glucose Transporter Type 1; D006801:Humans; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D027501:Monocarboxylic Acid Transporters / Q000096:biosynthesis / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis / Q000378:metabolism*; D011060:Poloxalene / Q000494:pharmacology* / Q000633:toxicity; D027981:Symporters / Q000096:biosynthesis / Q000378:metabolism*; D000099233:Monocarboxylate Transport Protein 1
D000963:Antimetabolites; D003847:Deoxyglucose; D005079:Excipients; D051272:Glucose Transporter Type 1; D019344:Lactic Acid; D027501:Monocarboxylic Acid Transporters; D009004:Monosaccharide Transport Proteins; D011060:Poloxalene; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C495677:SLC2A1 protein, human; C495678:Slc2a1 protein, mouse; C422648:pluronic block copolymer p85