scholarly journals Active participation of membrane lipids in inhibition of multidrug transporter P-glycoprotein

2021 ◽  
Author(s):  
Karan Kapoor ◽  
Shashank Pant ◽  
Emad Tajkhorshid
Keyword(s):  
Membrane Lipids ◽  
Active Participation ◽  
Multidrug Transporter ◽  
Glycoprotein P ◽  
P Glycoprotein

Lipid invasion of P-glycoprotein, enhanced by binding of an inhibitor.

scholarly journals Characterization and tissue localization of zebrafish homologs of the human ABCB1 multidrug transporter

2021 ◽  
Author(s):  
Robert W. Robey ◽  
Andrea N. Robinson ◽  
Fatima Ali-Rahmani ◽  
Lyn M. Huff ◽  
Sabrina Lusvarghi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Multidrug Transporter ◽  
Glycoprotein P ◽  
Tissue Localization ◽  
Brain Vasculature ◽  
P Glycoprotein ◽  
Capillary Endothelial Cells ◽  
The Brain ◽  
Viable Model

ABSTRACTGiven its similarities with mammalian systems, the zebrafish has emerged as a potential model to study the blood-brain barrier (BBB). Capillary endothelial cells at the human BBB express high levels of P-glycoprotein (P-gp, encoded by the ABCB1 gene) and ABCG2 (encoded by the ABCG2 gene). However, little information has been available about ATP-binding cassette transporters expressed at the zebrafish BBB. In this study, we focus on the characterization and tissue localization of two genes that are similar to human ABCB1, zebrafish abcb4 and abcb5. Cytotoxicity assays with stably-transfected cell lines revealed that zebrafish Abcb5 cannot efficiently transport the substrates doxorubicin and mitoxantrone compared to human P-gp and zebrafish Abcb4. Additionally, zebrafish Abcb5 did not transport the fluorescent probes BODIPY-ethylenediamine or LDS 751, while they were readily transported by Abcb4 and P-gp. A high-throughput screen conducted with 90 human P-gp substrates confirmed that zebrafish Abcb4 has overlapping substrate specificity with P-gp. Basal ATPase activity of zebrafish Abcb4 and Abcb5 was comparable to that of human P-gp. In the brain vasculature, RNAscope probes to detect abcb4 colocalized with staining by the P-gp antibody C219, while abcb5 was not detected. Zebrafish abcb4 also colocalized with claudin-5 expression in brain endothelial cells. Abcb4 and Abcb5 had different tissue localizations in multiple zebrafish tissues, consistent with different functions. The data suggest that zebrafish Abcb4 most closely phenocopies P-gp and that the zebrafish may be a viable model to study the role of the multidrug transporter P-gp at the BBB.

scholarly journals MEMANTINE, AS A P-GLYCOPROTEIN EXPRESSION MODULATOR, ENHANCES LEVETIRACETAM THERAPEUTIC RESPONSE IN EPILEPTIC PATIENTS

2020 ◽  
pp. 104-108
Author(s):  
SAHAR AHMED HARBY ◽  
RASHA A NASSRA ◽  
JAIDAA F MEKKY ◽  
SAMIA M ALI ◽  
CHERINE A ISMAIL
Keyword(s):  
Therapeutic Response ◽  
Seizure Control ◽  
Multidrug Transporter ◽  
Potential Therapeutic Target ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Epileptic Patients ◽  
Patients With Epilepsy ◽  
Transporter Expression

Objective: The principal aim of the present study was to assess the importance of multidrug transporter; P-glycoprotein (P-gp) as a potential therapeutic target in patients with epilepsy. Can P-gp transporter expression modulation by memantine add to the standard antiepileptic drugs (AEDs) response? Methods: A cohort of 56 epilepsy patients was included in a 4 monthly visits prospective study. Patients were on levetiracetam (LEV) 1000 mg/ day alone or combined with other AEDs. They were randomly assigned into two groups; LEV only group including LEV-treated patients and LEV + memantine group including patients on LEV with add-on oral memantine 10 mg/day until the end of the study. During monthly follow-up visits, therapeutic responses were evaluated for each patient by recording the monthly seizures frequency. Blood samples were drawn from every patient twice (on the first and last visits) for assessment of P-gp mRNA expression level. Results: Fifty patients completed the study. At the end of 4th month, LEV only group showed a non-significant decrease in P-gp expression and seizure frequency compared to the 1st month, whereas, in LEV + memantine group, P-gp expression was significantly reduced and associated with significant seizure control. Conclusion: Memantine by hindering P-gp overexpression was apt to enhance LEV efficacy and exhibit a better seizure control.

scholarly journals Studies of Human MDR1-MDR2 Chimeras Demonstrate the Functional Exchangeability of a Major Transmembrane Segment of the Multidrug Transporter and Phosphatidylcholine Flippase

1999 ◽  
Vol 19 (2) ◽  
pp. 1450-1459 ◽  
Author(s):  
Yi Zhou ◽  
Michael M. Gottesman ◽  
Ira Pastan
Keyword(s):  
Functional Relationship ◽  
Transmembrane Domain ◽  
Site Directed Mutagenesis ◽  
Multidrug Transporter ◽  
Transmembrane Segment ◽  
Glycoprotein P ◽  
Hydrophobic Compounds ◽  
Functional Differences ◽  
P Glycoprotein ◽  
Human Mdr1

ABSTRACT P-glycoprotein (P-gp), encoded by the MDR1 gene, is a plasma membrane transporter which effluxes a large number of structurally nonrelated hydrophobic compounds. The molecular basis of the broad substrate recognition of P-gp is not well understood. Despite the 78% amino acid sequence identity of the MDR1 andMDR2 transporter, MDR2, which has been identified as a phosphatidylcholine transporter, does not transport most MDR1 substrates. The structural and functional differences between MDR1 and MDR2 provide an opportunity to identify the residues essential for the broad substrate spectrum of MDR1. Using an approach involving exchanging homologous segments of MDR1 and MDR2 and site-directed mutagenesis, we have demonstrated that MDR1 residues Q330, V331, and L332 in transmembrane domain 6 are sufficient to allow an MDR2 backbone in the N-terminal half of P-gp to transport several MDR1 substrates, including bisantrene, colchicine, vinblastine, and rhodamine-123. These studies help define some residues important for multidrug transport and indicate the close functional relationship between the multidrug transporter (MDR1) and phosphatidylcholine flippase (MDR2).

Correlation between P-glycoprotein (P-gp) expression in parathyroid and Tc-99m MIBI parathyroid image findings

2001 ◽  
Vol 28 (8) ◽  
pp. 929-933 ◽  
Author(s):  
Shung-Shung Sun ◽  
Yu-Chien Shiau ◽  
Cheng-Chieh Lin ◽  
Albert Kao ◽  
Cheng-Chun Lee
Keyword(s):  
Glycoprotein P ◽  
P Glycoprotein

Molecular docking studies of tea (Thea sinensis Linn.) polyphenols inhibition pattern with Rat P-glycoprotein

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Babar Ali ◽  
Qazi Mohammad Sajid Jamal ◽  
Showkat R. Mir ◽  
Saiba Shams ◽  
Mohammad Amjad Kamal
Keyword(s):  
Amino Acids ◽  
Molecular Docking ◽  
Binding Energy ◽  
Oral Administration ◽  
Docking Studies ◽  
Vital Role ◽  
Glycoprotein P ◽  
High Affinity ◽  
P Glycoprotein ◽  
Inhibition Pattern

AbstractSince 3000 B.C., evergreen plant Thea sinensis (Theaceae) is used both as a social and medicinal beverage. Leaves of T. sinensis contain amino acids, vitamins, caffeine, polysaccharides and polyphenols. Most of the natural medicinal actions of tea are due to the availability and abundance of polyphenols mainly catechins. It has also been stated that some catechins were absorbed more rapidly than other compounds after the oral administration of tea and could increase the bio-enhancing activities of anticancer drugs by inhibiting P-glycoprotein (P-gp). The results of the molecular docking showed that polyphenols bind easily to the active P-gp site. All compounds exhibited fluctuating binding affinity ranged from −11.67 to −8.36 kcal/mol. Observed binding energy required for theaflavin to bind to P-gp was lowest (−11.67 kcal/mol). The obtained data that supports all the selected polyphenols inhibited P-gp and therefore may enhance the bioavailability of drugs. This study may play a vital role in finding hotspots in P-gp and eventually may be proved useful in designing compounds with high affinity and specificity to the protein.

scholarly journals Co-Amorphous Formulations of Furosemide with Arginine and P-Glycoprotein Inhibitor Drugs

Pharmaceutics ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 171
Author(s):  
Marika Ruponen ◽  
Konsta Kettunen ◽  
Monica Santiago Pires ◽  
Riikka Laitinen
Keyword(s):  
Storage Conditions ◽  
Scanning Calorimetry ◽  
Glycoprotein P ◽  
Molar Ratios ◽  
P Glycoprotein ◽  
Permeation Studies ◽  
Poorly Soluble ◽  
Biopharmaceutics Classification ◽  
Permeability Assay ◽  
Simultaneous Dissolution

In this study, the amino acid arginine (ARG) and P-glycoprotein (P-gp) inhibitors verapamil hydrochloride (VER), piperine (PIP) and quercetin (QRT) were used as co-formers for co-amorphous mixtures of a Biopharmaceutics classification system (BCS) class IV drug, furosemide (FUR). FUR mixtures with VER, PIP and QRT were prepared by solvent evaporation, and mixtures with ARG were prepared by spray drying in 1:1 and 1:2 molar ratios. The solid-state properties of the mixtures were characterized with X-ray powder diffraction (XRPD), Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) in stability studies under different storage conditions. Simultaneous dissolution/permeation studies were conducted in side-by-side diffusion cells with a PAMPA (parallel artificial membrane permeability assay) membrane as a permeation barrier. It was observed with XRPD that ARG, VER and PIP formed co-amorphous mixtures with FUR at both molar ratios. DSC and FTIR revealed single glass transition values for the mixtures (except for FUR:VER 1:2), with the formation of intermolecular interactions between the components, especially salt formation between FUR and ARG. The co-amorphous mixtures were found to be stable for at least two months under an elevated temperature/humidity, except FUR:ARG 1:2, which was sensitive to humidity. The dissolution/permeation studies showed that only the co-amorphous FUR:ARG mixtures were able to enhance both the dissolution and permeation of FUR. Thus, it is concluded that formulating co-amorphous salts with ARG may be a promising option for poorly soluble/permeable FUR.

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