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Impact of molecular weight on the mechanism of cellular uptake of polyethylene glycols (PEGs) with particular reference to P-glycoprotein
- Source :
- Acta Pharmaceutica Sinica. B, Acta Pharmaceutica Sinica B, Vol 10, Iss 10, Pp 2002-2009 (2020)
- Publication Year :
- 2019
-
Abstract
- Polyethylene glycols (PEGs) in general use are polydisperse molecules with molecular weight (MW) distributed around an average value applied in their designation e.g., PEG 4000. Previous research has shown that PEGs can act as P-glycoprotein (P-gp) inhibitors with the potential to affect the absorption and efflux of concomitantly administered drugs. However, questions related to the mechanism of cellular uptake of PEGs and the exact role played by P-gp has not been addressed. In this study, we examined the mechanism of uptake of PEGs by MDCK-mock cells, in particular, the effect of MW and interaction with P-gp by MDCK-hMDR1 and A549 cells. The results show that: (a) the uptake of PEGs by MDCK-hMDR1 cells is enhanced by P-gp inhibitors; (b) PEGs stimulate P-gp ATPase activity but to a much lesser extent than verapamil; and (c) uptake of PEGs of low MW (5000 Da) occurs by a combination of passive diffusion and caveolae-mediated endocytosis. These findings suggest that PEGs can engage in P-gp-based drug interactions which we believe should be taken into account when using PEGs as excipients and in PEGylated drugs and drug delivery systems.<br />Graphical abstract PEGs are taken up by cells and act as P-gp substrates. Low molecular weight (MW) PEGs cross cell membranes by passive diffusion, whereas those high MW PEGs enter cells by a combination of passive diffusion and caveolae-mediated endocytosis.Image 1
- Subjects :
- NBD, nucleotide binding domain
Passive diffusion
DMSO, dimethyl sulfoxide
MW, molecular weight
CE, collision energy
LC−HRMS/MS, liquid chromatography−high resolution tandem mass spectrometry
chemistry.chemical_compound
0302 clinical medicine
P-gp, P-glycoprotein
IS, internal standard
General Pharmacology, Toxicology and Pharmaceutics
media_common
P-glycoprotein
0303 health sciences
DMEM, Dulbecco's modified Eagle's medium
biology
Chemistry
DDS, drug delivery system
Polyethylene
Endocytosis
030220 oncology & carcinogenesis
Drug delivery
Efflux
DP, declustering potential
PEGs
CsA, cyclosporine A
Drug
media_common.quotation_subject
Short Communication
Absorption (skin)
macromolecular substances
DBD, drug-binding domain
Cmax, maximum plasma concentration
03 medical and health sciences
FBS, fetal bovine serum
PEG ratio
PAC, paclitaxel
VER, verapamil
030304 developmental biology
PEG, polyethylene glycol
lcsh:RM1-950
technology, industry, and agriculture
HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
ACN, acetonitrile
HBSS, Hanks' balanced salt solution
lcsh:Therapeutics. Pharmacology
AUC, area under the plasma concentration-time curve
biology.protein
Biophysics
P-gp
P-gp-substrate
Subjects
Details
- ISSN :
- 22113835
- Volume :
- 10
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Acta pharmaceutica Sinica. B
- Accession number :
- edsair.doi.dedup.....67944d5d71e648ebb23f796d4bcd2c2c